Process for the preparation of substituted oxiranes and triazoles

ABSTRACT

The present invention relates to a process for the preparation of the compounds II 
                         
from the respective oxo compounds. Furthermore, he invention relates to a process for the preparation of triazole compounds from oxiranes II.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/759,779, filed Jul. 8, 2015, the entire contents of which is herebyincorporated herein by reference. U.S. application Ser. No. 14/759,779,is a National Stage application of International Application No.PCT/EP2013/077083, filed Dec. 18, 2013 the entire contents of which ishereby incorporated herein by reference. U.S. application Ser. No.14/759,779 also claims priority under 35 U.S.C. § 119 to European PatentApplication No. 13150663.6, filed Jan. 9, 2013; European PatentApplication No. 13195331.7, filed Dec. 2, 2013; and European PatentApplication No. 13196978.4, filed Dec. 12, 2013, the entire contents ofwhich are hereby incorporated herein by reference.

DESCRIPTION

The present invention relates to a process for providing oxiranes usingan aqueous solution of trimethylsulfonium methylsulfate in the presenceof a base, and optionally further converting the resulting oxiranes intotriazole compounds by reacting the substituted oxiranes with1H-1,2,4-triazole under basic conditions. Further, the invention relatesto a process for providing certain substituted triazoles. Furthermore,the invention relates to an aqueous reagent of trimethylsulfoniummethylsulfate and its use for the conversion of oxo-groups intooxiranes.

The substituted oxiranes provided by the process according to thepresent invention are valuable intermediate compounds for the synthesisof triazole compounds having pesticidal, in particular fungicidalactivity. Triazole compounds that are accessible via an oxiraneintermediate are, for example described in WO 2013/010862(PCT/EP2012/063526), WO 2013/010894 (PCT/EP2012/063635), WO 2013/010885(PCT/EP2012/063620), WO 2013/024076 (PCT/EP2012/065835), WO 2013/024075(PCT/EP2012/065834), WO 2013/024082 (PCT/EP2012/065850), WO 2013/024077(PCT/EP2012/065836), WO 2013/024081 (PCT/EP2012/065848), WO 2013/024080(PCT/EP2012/065847), WO 2013/024083 (PCT/EP2012/065852) and EP 2559688(EP 11177556.5), that are directed to specific fungicidal substituted2-[2-halogen-4-phenoxy-phenyl]-1-[1,2,4]triazol-1-yl-ethanol compounds.WO 2013/007767 (PCT/EP2012/063626) is directed to fungicidal substituted2-[2-halogenalkyl-4-phenoxy-phenyl]-1-[1,2,4]triazol-1-yl-ethanolcompounds, that can also be synthesized via a respective oxiraneintermediate compound. A common process for the synthesis of oxiranesfrom carbonyl compounds such as aldehydes and ketones is the reactionwith trimethylsulfonium iodide in the presence of a base (JACS 1965, 87,p 1353ff). This reagent is very expensive and not suitable forindustrial scales. An alternative reagent is trimethylsulfoniummethylsulfate that can be obtained from dimethylsulfide anddimethylsulfate (Heterocycles 8, 1977, p. 397 ff). However, this reagent(melting point 100 to 104° C.) is very hygroscopic and difficult tohandle in solid form (Synth. Communications, 15, 1985, p 753). Forexample an exact dosage of said reagent is only possible under theexclusion of atmospheric humidity. In J. Agric. Food Chem. 2009, 57,4854-4860 certain2-arylphenyl-ether-3-(1H-1,2,4-triazol-1-yl)propan-2-ol derivatives aresynthesized via an oxirane.

Synthetic Communications 15, 1985, p. 749ff. generally describes thereaction of trimethylsulfonium methyl sulfate with aldehydes and ketonesusing 50% NaOH solution. However, not with every ketone or aldehyde,satisfying yields can be achieved, in particular, aldehydes that aremore reactive are reacted. According to this document, NaOH is used asbase for the reaction and high amounts of water are used because thebase is added as 50% aqueous solution. Furthermore, high excess of baseand preferably methylenechloride are used in the process, which is notsuitable for an industrial process also because of environmental issues.

A. A. Afonkin et al. In the Russian Journal of Organic Chemistry, vol.44, no. 12, 2008, pp 1776 to 1779, is directed to the synthesis of someelectron-rich aryl (heteroaryl) oxiranes under phase-transfer andhomogenous conditions using trimethylsulfonium methyl sulfate asreagent. In this reference, the reaction of aldehydes is described thatare generally more reactive than ketones. NaOH is used as 50% aqueoussolution, i.e. high amounts of water are present.

DE3733755 is directed to a process for the preparation of2-(4-chlorophenyl-ethyl)-2-tert-butyl-oxirane from the respective ketoneusing trimethylsulfonium methylfulfate in the presence of potassiumhydroxide, dimethylsulfide and water. According to this document, theamount of water present in the reaction must be between 1.0 and 1.5 moleper mole of ketone, otherwise the yields are not high enough. Suchrestricted amounts of water are, however, not favorable for anindustrial process.

Consequently, the methods known from the literature are sometimes notsuitable for the efficient synthesis of substituted oxiranes because theyield is not sufficient and/or the reaction conditions and parameterssuch as water content and/or the proportion of the reactants andingredients to each other are not suitable for an upscale toindustrially relevant amounts. Inter alia because some oxiranes arevaluable intermediates for the synthesis of triazole compounds withpromising fungicidally activity, there is an ongoing need for improvedprocesses that easily make such intermediates and compounds available.

An object of the present invention was to provide an improved processfor the synthesis of oxiranes that are valuable intermediates for thepreparation of fungicidal active triazole compounds starting from therespective oxo-group containing compounds. Furthermore, the objectunderlying the present invention was to optimize the synthesis oftriazole active compounds using said oxiranes.

It has now surprisingly been found a highly efficient synthesis for theconversion of specific oxo-group containing compounds into oxiranes thatare useful as intermediates in the synthesis of certain pesticidaltriazole compounds.

Accordingly, one aspect of the present invention is a process for thepreparation of compounds IIa

wherein R^(G) is optionally substituted aryl or heteroaryl and R¹ is asdefined below;

comprising the following step:

-   (i) reacting an oxo compound of the formula IIIa

with trimethylsulfonium methylsulfate of the formula IV(CH₃)₃S⁺CH₃SO₄ ⁻  IVin aqueous solution in the presence of a base.

In particular, in the inventive process, compound IIa is oxiranecompound II and compound IIIa is oxo-compound III. Consequently, thepresent invention particularly relates to a process for the preparationof the compounds II

comprising the following step:

-   (i) reacting an oxo compound of the formula III

with trimethylsulfonium methylsulfate of the formula IV(CH₃)₃S⁺CH₃SO₄ ⁻  IVin aqueous solution in the presence of KOH, wherein 1 to 4, preferablymore than 1.5 equivalents to 4 equivalents of water in relation to oneequivalent of compound III are used, wherein the variables R¹, R³, R⁴, nand m are defined as follows:

-   R¹ is selected from C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, phenyl,    phenyl-C₁-C₄-alkyl, phenyl-C₂-C₄-alkenyl or phenyl-C₂-C₄-alkynyl;-   wherein the aliphatic moieties of R¹ are not further substituted or    do carry one, two, three or up to the maximum possible number of    identical or different groups R^(12a) which independently are    selected from:-   R^(12a) halogen, OH, CN, nitro, C₁-C₄-alkoxy, C₃-C₈-cycloalkyl,    C₃-C₈-halocycloalkyl and C₁-C₄-halogenalkoxy;-   wherein the cycloalkyl and/or phenyl moieties of R¹ are not further    substituted or do carry one, two, three, four, five or up to the    maximum number of identical or different groups R^(12b) which    independently are selected from:-   R^(12b) halogen, OH, CN, nitro, C₁-C₄-alkyl, C₁-C₄-alkoxy,    C₁-C₄-halogenalkyl, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl and    C₁-C₄-halogenalkoxy-   R³ is independently selected from halogen, CN, NO₂, OH, SH,    C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyloxy, NH₂, NH(C₁-C₄-alkyl),    N(C₁-C₄-alkyl)₂, NH(C₃-C₆-cycloalkyl), N(C₃-C₆-cycloalkyl)₂,    S(O)_(p)(C₁-C₄-alkyl), C(═O)(C₁-C₄-alkyl), C(═O)(OH),    C(═O)(O—C₁-C₄-alkyl), C(═O)(NH(C₁-C₄-alkyl)),    C(═O)(N(C₁-C₄-alkyl)₂), C(═O)(NH(C₃-C₆-cycloalkyl)) and    C(═O)—(N(C₃-C₆-cycloalkyl)₂); wherein each of R³ is unsubstituted or    further substituted by one, two, three or four R^(3a); wherein p is    0, 1 or 2, and wherein-   R^(3a) is independently selected from halogen, CN, NO₂, OH,    C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₈-cycloalkyl,    C₃-C₈-halocycloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy;-   R⁴ is independently selected from the substituents as defined for    R³, wherein said R⁴ are unsubstituted or further substituted by one,    two, three or four R^(4a), wherein each R^(4a) is independently    selected from the substituents as defined for R^(3a);-   n is 0, 1, 2, 3 or 4; and-   m is 0, 1, 2, 3, 4 or 5.

More specifically, compounds II and III are the following:

wherein R is selected from halogen and (C₁-C₂)-haloalkyl, in particularCl, Br, F or CF₃, more specifically Cl or CF₃, and R¹, R³, R⁴ and m areas defined and preferably defined herein, and n1 is 0, 1, 2 or 3.

In one embodiment, the compounds of formula III are of sub formula IIIA

wherein R¹ is C₁-C₆-alkyl or C₃-C₈-cycloalkyl and R⁴ is F or Cl.

According to one embodiment, R¹ is C₁-C₆-alkyl, more specificallyC₁-C₄-alkyl, in particular selected from CH₃, C₂H₅, n-C₃H₇, CH(CH₃)₂,n-butyl, iso-butyl and tert-butyl, more particularly selected from CH₃,C₂H₅, CH(CH₃)₂ and C(CH₃)₃. According to a further embodiment, R¹ isC₃-C₈-cycloalkyl, in particular C₃-C₆-cycloalkyl, such as C₃H₅(cyclopropyl), C₄H₇ (cyclobutyl), cyclopentyl or cyclohexyl. A furtherembodiment relates to compounds, wherein R¹ is C₃H₅ (cyclopropyl) orC₄H₇ (cyclobutyl).

R⁴ is F or Cl, in particular Cl.

In particular, R¹ is selected from CH₃, CH(CH₃)₂ and cyclopropyl and R⁴is Cl.

This embodiment applies to formula II and I accordingly:

with the above meanings of R¹ and R⁴.

In the process step (i) according to the present invention, an oxocompound of the formula III is reacted with trimethylsulfoniummethylsulfate of the formula IV(CH₃)₃S⁺CH₃SO₄ ⁻  IVin aqueous solution in the presence of a base.

Preferably, in the inventive process, 1 to 4 equivalents, in particular1.2 to 3.5 eq, more specifically 1.5 to 3.3 eq, of water in relation toone equivalent of compound III are used. It may be favorable, if morethan 1.5 eq of water, in particular more than 1.5 eq of water to 4 eq ofwater, more specifically more than 1.5 eq to 3.5 eq of water, even moreparticularly more than 1.5 eq water to 2.5 eq water per mole of compoundIII. In particular the ratios of 1.6 to 3.8, more specifically 1.7 to3.3 eq, more specifically 1.8 to 2.8 eq or 1.9 to 2.5 of water per moleof compound III may be favorable according to the present invention.

The reagent IV is preferably used in an amount of 1.1 to 2.5, inparticular 1.2 to 2, more specifically 1.3 to 1.6 equivalents of IV per1 equivalent (mole) of compound III.

In general, the reagent of formula IV can be prepared fromdimethylsulfide and dimethylsulfate. According to one embodiment of theinvention, reagent IV is prepared in-situ by adding dimethylsulfate tothe reaction mixture containing dimethylsulfide. The dimethylsulfide isusually used in excess.

It is preferred according to the present invention to use as reagent IVan aqueous solution of trimethylsulfonium methylsulfate III containing33 to 37 wt %, preferably 34 to 36 wt %, more specifically 34 to 35.3 wt%, also more specifically 34.3 to 35.9 wt %, of trimethylsulfoniumkation.

Such stable aqueous solutions of the reagents are novel. Thus, accordingto a further aspect, the present invention relates to an aqueoussolution of trimethylsulfonium methylsulfate III containing 33 to 37 wt%, preferably 34 to 36 wt %, more specifically 34 to 35.3 wt %, alsomore specifically 34.3 to 35.9 wt %, of trimethylsulfonium kation.

In particular, the inventive reagent IV solution contains 33 to 37 wt %,preferably 34 to 36 wt %, more specifically 34 to 35.3 wt %, also morespecifically 34.3 to 35.9 wt %, of trimethylsulfonium kation.Accordingly, the amount of trimethylsulfonium-methylsulfate in thereagent, measured as summation of trimethsulfonium-cation andmethylsulfate-anion, is about 80 to 90 wt %, preferably about 83 to 88wt-%, more specifically about 83 to 86 wt-%. The quantification can be,for example, accomplished by means of quantitative NMR-spectroscopie.

The viscosity of the aqueous reagent IV solution of the invention iscomparatively low. The inventive solutions are stable at roomtemperature, in particular at 25° C., and can be stored over a longertime. In particular, the inventive reagent solution does not crystallizeout during storage over a longer time, such as several weeks, e.g. up to12 weeks, at temperatures of 10 to 25° C.

The reagent can be prepared by adding dimethylsulfate to water anddimethylsulfide. Dimethylsulfide is normally used in excess, generally 2to 8, more preferably 4 to 6, more specifically 4.5 to 5.5, equivalents.

In the preparation of the aqueous solution of reagent IV according tothe invention, preferably 1.3 to 2.2 eq, more preferably 1.45 to 2.0 eq,water in relation to the dimethylsulfate are used.

Preferably, the temperature of the reaction mixture when adding thedimethylsulfate is room temperature, in particular 25° C. to 40° C.

The aqueous reagent separates as the lower phase and can be further usedas such.

Following the state of the art, it was not possible to provide stableaqueous solutions of reagent IV that can be used in process for thesynthesis of oxiranes from oxo-group containing compounds. It has nowsurprisingly been found within the framework of the present inventionthat stable aqueous solution of reagent IV can be provided if specificranges of water as defined above in relation to the dimethylsulfate arekept.

Thus, another aspect of the invention is the general use of theinventive aqueous solution of trimethylsulfonium methylsulfate IV forthe synthesis of an oxirane from the respective oxo compound, inparticular a compound IIa from a compounds IIIa, more specifically acompound II from a compound III as defined herein.

The use of the inventive aqueous solution of the reagent IV has beenproven very efficient also for upscaled reaction conditions, since it isstable and since it contains a defined amount of reagent, so thatreagent IV can be easily and precisely dosed to the reaction mixture.

Thus it is a preferred embodiment, if in step (i) of the inventiveprocess, the reagent IV is added as an aqueous solution oftrimethylsulfonium methylsulfate III containing 33 to 37 wt %,preferably 34 to 36 wt %, more specifically 34 to 35.3 wt %, also morespecifically 34.3 to 35.9 wt % of trimethylsulfonium kation or anypreferred embodiment thereof defined herein.

The base used in step (i) according to the invention is preferablyselected from KOH and NaOH In a preferred embodiment, KOH is used andspecifically, it is used in solid form, preferably as solid pellets,flakes, microprills and/or powder. It is preferred if at least 3equivalents of base, preferably at least 3.2 eq, more specifically atleast 3.4 eq per 1 equivalent of compound III are used. It may bepreferred if the amount of base is 3 to 6 eq, more specifically 3 to 5eq per mole of compound III.

The base, in particular solid KOH, is used such that the inventive rangeof water present in the reaction is kept. Then, some of the base isdissolved in the reaction solution and some is still present in solidform during the reaction.

According to one embodiment of the inventive process, dimethylsulfide isalso used as solvent in step (i). According to a further embodiment, anadditional solvent is used. In particular, an aprotic organic solvent issuitable, such as for example diethylether, methyl-tert-butylether,chlorobenzene, xylene or toluene.

The reaction temperature in step (i) is preferably held at a maximum of50° C., in particular at a maximum of 45, more preferably at a maximumof 40° C. Generally, it is also preferred to have a reaction temperatureof at least 20° C., in particular at least room temperature, inparticular at least 25° C. In a further embodiment, the temperature isat least 30° C. It may be preferred if the temperature is at least 35°C.

By means of the inventive process, the oxiranes of formula II can beprepared in high yields. Preferably, the yields are at least 60%, morepreferably 70%, even more preferred at least 75%, even more preferred atleast 80%.

The order of adding the reactants to the reaction mixture is variable.In one embodiment, the base is added to the solution of compound III andsolvent first and then reagent IV is added. According to anotherembodiment, the reagent IV is added first to the solution of compoundIII and then the base is added. According to a further embodiment, asolution of compound III and the reagent IV are added simultaneously tothe base. In the latter embodiment, the base is preferably suspended insufficient solvent and is stirred during the addition of the reagents.

The oxirane obtained according to the inventive process (step (i)) canbe further converted into a triazole of formula I. Consequently,according to a further embodiment of the invention, the process furthercomprises the following step:

-   (ii) reacting the oxirane of the formula II resulting from step (i)    with 1H-1,2,4-triazole and an inorganic base, resulting in compounds    of formula I,

In step (ii), the oxirane is reacted with 1H-1,2,4-triazole and aninorganic base.

The inorganic base used in step (ii) is preferably selected from NaOH,KOH, Na₂CO₃ and K₂CO₃, more specifically from NaOH and KOH. According toone embodiment, NaOH is used. According to a further embodiment, KOH isused.

According to a specific embodiment, the sodium salt of 1H-1,2,4-triazoleas a base is used, wherein said sodium salt is prepared using triazoleand a base preferably selected from NaOH, NaH and Na-alcoholates. Seealso DE 3042302.

The amount of base used in step (ii) is preferably equal to or less than1 eq, in particular less than 1 eq, more preferably equal to or lessthan 0.8 eq, even more preferably equal to or less than 0.6 equivalentsper 1 equivalent of compound II. Also preferred are amounts of basebeing equal to or less than 0.4 equivalents, in particular equal to orless than 0.2 equivalents, specifically equal to or less than 0.1 eq per1 equivalent of compound II. Preferably, at least 0.1 eq, morepreferably at least 0.2 equivalents, in particular at least 0.3, morespecifically at least 0.4 eq base per 1 equivalent of compound II areused.

It has surprisingly been found according to the invention, that higheryields of compounds I can be achieved, if less than 1 eq of base is usedin relation to the compound II. In specific embodiments thereof, NaOH isused in as base, preferably in an amount as given above, in particularin an amount of 0.1 to 0.55 eq in relation to the oxirane of formula II.

In order to have preferably low reaction times, temperatures of at least100° C., more preferably at least 110° C., in particular at least 120°C. are favorable. It is also an embodiment to reflux the reactionmixture. Preferably, the reaction temperature is not higher than 150°C., in particular not higher than 140° C. Specifically, a reactiontemperature of 120° C. to 140° C. is used.

The amount of 1H-1,2,4-triazole used in step (ii) generally is at least1 eq per mole of oxirane II. According to one embodiment, the1H-1,2,4-triazole is used in excess in relation to the oxirane II.Preferred are more than 1 eq to 2 eq, more preferably more than 1 eq to1.8 eq, even more preferred more than 1 eq to 1.6 eq. Mostly foreconomic reason, it can be preferred to use at least 1.1 eq,specifically 1.15 eq, to 1.5 eq of triazole in relation to oxirane II.

The solvent used in step (ii) is preferably selected fromdimethylformamide, dimethylacetamide, N-metylpyrrolidone. Most preferredis dimethylformamide.

One side product that may occur, if R¹ is iso-propyl is the followingcompound II″, more specifically IIa″:

wherein R³, R⁴, n and m are defined above. In particular, in formulaIIa″, R³ is CF₃ or Cl and R⁴ is Cl.

According to the inventive process conditions, the side product can berepressed or avoided and higher yields can be obtained.

Generally, one further undesired side product in the synthesis ofcompounds I that may occur in undesired amounts is the symmetrictriazole I″ that is formed together with the desired triazole of formulaI, sometimes in high excess compared to the desired compound I, leading,consequently, to lower yields of the desired product of formula I.

wherein R¹, R³, R⁴, n and m are defined above. In particular Ia″ mayoccur, wherein R³ is R³ is CF₃ or Cl and R⁴ is Cl and R¹ is as definedand preferably defined herein:

Particular side products Ia″ that may occur during the inventive processdepending on the substituents in the reagents are compiled in Table S1.Each line of lines S1-1 to S1-320 of Table S1 corresponds to a sideproduct Ia″ having the substituents specified in the respective line:

TABLE S1 I″ No. R⁴ R³ R¹ S1-1 Cl CF₃ H S1-2 Cl CF₃ CH₃ S1-3 Cl CF₃CH₂CH₃ S1-4 Cl CF₃ CH₂CH₂CH₃ S1-5 Cl CF₃ CH(CH₃)₂ S1-6 Cl CF₃ C(CH₃)₃S1-7 Cl CF₃ CH(CH₃)CH₂CH₃ S1-8 Cl CF₃ CH₂CH(CH₃)₂ S1-9 Cl CF₃CH₂CH₂CH₂CH₃ S1-10 Cl CF₃ CF₃ S1-11 Cl CF₃ CHF₂ S1-12 Cl CF₃ CH₂F S1-13Cl CF₃ CHCl₂ S1-14 Cl CF₃ CH₂Cl S1-15 Cl CF₃ CH₂OH S1-16 Cl CF₃ CH₂CH₂OHS1-17 Cl CF₃ CH₂CH₂CH₂OH S1-18 Cl CF₃ CH(CH₃)CH₂OH S1-19 Cl CF₃CH₂CH(CH₃)OH S1-20 Cl CF₃ CH₂CH₂CH₂CH₂OH S1-21 Cl CF₃ CH(CH₃)CN S1-22 ClCF₃ CH₂CH₂CN S1-23 Cl CF₃ CH₂CN S1-24 Cl CF₃ CH₂CH₂CN S1-25 Cl CF₃CH₂CH₂CH₂CN, S1-26 Cl CF₃ CH(CH₃)CH₂CN S1-27 Cl CF₃ CH₂CH(CH₃)CN S1-28Cl CF₃ CH₂CH₂CH₂CH₂CN S1-29 Cl CF₃ CH₂OCH₃ S1-30 Cl CF₃ CH₂OCH₂CH₃ S1-31Cl CF₃ CH(CH₃)OCH₃ S1-32 Cl CF₃ CH(CH₃)OCH₂CH₃ S1-33 Cl CF₃CH₂CH₂OCH₂CH₃ S1-34 Cl CF₃ CH₂OCF₃ S1-35 Cl CF₃ CH₂CH₂OCF₃ S1-36 Cl CF₃CH₂OCCl₃ S1-37 Cl CF₃ CH₂CH₂OCCl₃ S1-38 Cl CF₃ CH═CH₂ S1-39 Cl CF₃CH₂CH═CH₂ S1-40 Cl CF₃ CH₂CH═CHCH₃ S1-41 Cl CF₃ CH₂C(CH₃)═CH₂ S1-42 ClCF₃ CH₂C(CH₃)═CHCH₃ S1-43 Cl CF₃ CH₂C(CH₃)═C(CH₃)₂ S1-44 Cl CF₃ CH═CHCH₃S1-45 Cl CF₃ C(CH₃)═CH₂ S1-46 Cl CF₃ CH═C(CH₃)₂ S1-47 Cl CF₃C(CH₃)═C(CH₃)₂ S1-48 Cl CF₃ C(CH₃)═CH(CH₃) S1-49 Cl CF₃ C(Cl)═CH₂ S1-50Cl CF₃ C(H)═CHCl S1-51 Cl CF₃ C(Cl)═CHCl S1-52 Cl CF₃ CH═CCl₂ S1-53 ClCF₃ C(Cl)═CCl₂ S1-54 Cl CF₃ C(H)═CH(F) S1-55 Cl CF₃ C(H)═CF₂ S1-56 ClCF₃ C(F)═CF₂ S1-57 Cl CF₃ C(F)═CHF S1-58 Cl CF₃ CH═CHCH₂OH S1-59 Cl CF₃CH═CHOCH₃ S1-60 Cl CF₃ CH═CHCH₂OCH₃ S1-61 Cl CF₃ CH═CHCH₂OCF₃ S1-62 ClCF₃ CH═CHCH₂OCCl₃ S1-63 Cl CF₃ CH═CH(C₃H₅) S1-64 Cl CF₃ CH═CH(C₄H₇)S1-65 Cl CF₃ CH═CH(1-Cl—C₃H₄) S1-66 Cl CF₃ CH═CH(1-F—C₃H₄) S1-67 Cl CF₃CH═CH(1-Cl—C₄H₆) S1-68 Cl CF₃ CH═CH(1-F—C₄H₆) S1-69 Cl CF₃ C≡CH S1-70 ClCF₃ C≡CCH₃ S1-71 Cl CF₃ CH₂C≡CCH₃ S1-72 Cl CF₃ CH₂C≡CH S1-73 Cl CF₃CH₂C≡CCH₂CH₃ S1-74 Cl CF₃ C≡CCH(CH₃)₂ S1-75 Cl CF₃ C≡CC(CH₃)₃ S1-76 ClCF₃ C≡C(C₃H₅) S1-77 Cl CF₃ C≡C(C₄H₇) S1-78 Cl CF₃ C≡C(1-Cl—C₃H₄) S1-79Cl CF₃ C≡C(1-Cl—C₄H₆) S1-80 Cl CF₃ C≡CCl S1-81 Cl CF₃ C≡CBr S1-82 Cl CF₃C≡C—I S1-83 Cl CF₃ CH₂C≡CCl S1-84 Cl CF₃ CH₂C≡CBr S1-85 Cl CF₃ CH₂C≡C—IS1-86 Cl CF₃ C≡CCH₂OCH₃ S1-87 Cl CF₃ C≡CCH(OH)CH₃ S1-88 Cl CF₃C≡CCH(OCH₃)CH₃ S1-89 Cl CF₃ C≡COCH₃ S1-90 Cl CF₃ CH₂C≡COCH₃ S1-91 Cl CF₃C≡CCH₂OCCl₃ S1-92 Cl CF₃ C≡CCH₂OCF₃ S1-93 Cl CF₃ C≡CCH₂(C₃H₅) S1-94 ClCF₃ C≡CCH₂(C₄H₇) S1-95 Cl CF₃ C≡C(1-Cl—C₃H₄) S1-96 Cl CF₃ C≡C(1-F—C₃H₄)S1-97 Cl CF₃ C≡C(1-Cl—C₄H₆) S1-98 Cl CF₃ C≡C(1-F—C₄H₆) S1-99 Cl CF₃ C₃H₅(cyclopropyl) S1-100 Cl CF₃ C₄H₇ (cyclobutyl) S1-101 Cl CF₃ C₅H₉(cyclopentyl) S1-102 Cl CF₃ cyclohexyl S1-103 Cl CF₃ CH(CH₃)—C₃H₅(CH(CH₃)-cyclopropyl) S1-104 Cl CF₃ CH₂—C₃H₅ (CH₂-cyclopropyl) S1-105 ClCF₃ 1-(Cl)-cyclopropyl S1-106 Cl CF₃ 1-(F)-cyclopropyl S1-107 Cl CF₃1-(CH₃)-cyclopropyl S1-108 Cl CF₃ 1-(CN)-cyclopropyl S1-109 Cl CF₃2-(Cl)-cyclopropyl S1-110 Cl CF₃ 2-(F)-cyclopropyl S1-111 Cl CF₃1-(Cl)-cyclobutyl S1-112 Cl CF₃ 1-(F)-cyclobutyl S1-113 Cl CF₃2-(Cl)-cyclobutyl S1-114 Cl CF₃ 3-(Cl)-cyclobutyl S1-115 Cl CF₃2-(F)-cyclobutyl S1-116 Cl CF₃ 3-(F)-cyclobutyl S1-117 Cl CF₃3,3-Cl₂-cyclobutyl S1-118 Cl CF₃ 3,3-F₂-cyclobutyl S1-119 Cl CF₃2-(CH₃)-cyclopropyl S1-120 Cl CF₃ 1-(CH₃)-cyclobutyl S1-121 Cl Cl2-(CH₃)-cyclobutyl S1-122 Cl Cl 3-(CH₃)-cyclobutyl S1-123 Cl Cl3,3-(CH₃)₂-cyclobutyl S1-124 Cl Cl 2-(CN)-cyclopropyl S1-125 Cl Cl1-cyclopropyl-cyclopropyl S1-126 Cl Cl 2-cyclopropyl-cyclopropyl S1-127Cl Cl CH(CH₃)(cyclobutyl) S1-128 Cl Cl CH₂-(cyclobutyl) S1-129 Cl ClCH₂CH₂-(cyclopropyl) S1-130 Cl Cl CH₂CH₂-(cyclobutyl) S1-131 Cl ClCH₂-(1-Cl-cyclopropyl) S1-132 Cl Cl CH₂-(1-F-cyclopropyl) S1-133 Cl ClCH₂-(1-Cl-cyclobutyl) S1-134 Cl Cl CH₂-(1-F-cyclobutyl) S1-135 Cl ClCHCH₃-(1-Cl-cyclopropyl) S1-136 Cl Cl C(CH₃)₂-(1-F-cyclopropyl) S1-137Cl Cl C₆H₅ S1-138 Cl Cl 4-Cl—C₆H₄ S1-139 Cl Cl 4-OCH₃—C₆H₄ S1-140 Cl Cl4-CH₃—C₆H₄ S1-141 Cl Cl 4-F—C₆H₄ S1-142 Cl Cl 2,4-F₂—C₆H₃ S1-143 Cl Cl2,4-Cl₂—C₆H₃ S1-144 Cl Cl 2-CH₃—C₆H₄ S1-145 Cl Cl 2-CF₃—C₆H₄ S1-146 ClCl 4-CH₃—C₆H₄ S1-147 Cl Cl 4-CF₃—C₆H₄ S1-148 Cl Cl 2-OCH₃—C₆H₄ S1-149 ClCl 2-OCF₃—C₆H₄ S1-150 Cl Cl 4-OCH₃—C₆H₄ S1-151 Cl Cl 4-OCF₃—C₆H₄ S1-152Cl Cl 2,4,6-F₃—C₆H₂ S1-153 Cl Cl 2,4,6-Cl₃—C₆H₂ S1-154 Cl Cl CH₂C₆H₅S1-155 Cl Cl CH₂—(4-Cl)—C₆H₄ S1-156 Cl Cl CH₂—(4-CH₃)—C₆H₄ S1-157 Cl ClCH₂—(4-OCH₃)—C₆H₄ S1-158 Cl Cl CH₂—(4-F)—C₆H₄ S1-159 Cl ClCH₂—(2,4-Cl₂)—C₆H₃ S1-160 Cl Cl CH₂—(2,4-F₂)—C₆H₃ S1-161 Cl Cl H S1-162Cl Cl CH₃ S1-163 Cl Cl CH₂CH₃ S1-164 Cl Cl CH₂CH₂CH₃ S1-165 Cl ClCH(CH₃)₂ S1-166 Cl Cl C(CH₃)₃ S1-167 Cl Cl CH(CH₃)CH₂CH₃ S1-168 Cl ClCH₂CH(CH₃)₂ S1-169 Cl Cl CH₂CH₂CH₂CH₃ S1-170 Cl Cl CF₃ S1-171 Cl Cl CHF₂S1-172 Cl Cl CH₂F S1-173 Cl Cl CHCl₂ S1-174 Cl Cl CH₂Cl S1-175 Cl ClCH₂OH S1-176 Cl Cl CH₂CH₂OH S1-177 Cl Cl CH₂CH₂CH₂OH S1-178 Cl ClCH(CH₃)CH₂OH S1-179 Cl Cl CH₂CH(CH₃)OH S1-180 Cl Cl CH₂CH₂CH₂CH₂OHS1-181 Cl Cl CH(CH₃)CN S1-182 Cl Cl CH₂CH₂CN S1-183 Cl Cl CH₂CN S1-184Cl Cl CH₂CH₂CN S1-185 Cl Cl CH₂CH₂CH₂CN, S1-186 Cl Cl CH(CH₃)CH₂CNS1-187 Cl Cl CH₂CH(CH₃)CN S1-188 Cl Cl CH₂CH₂CH₂CH₂CN S1-189 Cl ClCH₂OCH₃ S1-190 Cl Cl CH₂OCH₂CH₃ S1-191 Cl Cl CH(CH₃)OCH₃ S1-192 Cl ClCH(CH₃)OCH₂CH₃ S1-193 Cl Cl CH₂CH₂OCH₂CH₃ S1-194 Cl Cl CH₂OCF₃ S1-195 ClCl CH₂CH₂OCF₃ S1-196 Cl Cl CH₂OCCl₃ S1-197 Cl Cl CH₂CH₂OCCl₃ S1-198 ClCl CH═CH₂ S1-199 Cl Cl CH₂CH═CH₂ S1-200 Cl Cl CH₂CH═CHCH₃ S1-201 Cl ClCH₂C(CH₃)═CH₂ S1-202 Cl Cl CH₂C(CH₃)═CHCH₃ S1-203 Cl ClCH₂C(CH₃)═C(CH₃)₂ S1-204 Cl Cl CH═CHCH₃ S1-205 Cl Cl C(CH₃)═CH₂ S1-206Cl Cl CH═C(CH₃)₂ S1-207 Cl Cl C(CH₃)═C(CH₃)₂ S1-208 Cl Cl C(CH₃)═CH(CH₃)S1-209 Cl Cl C(Cl)═CH₂ S1-210 Cl Cl C(H)═CHCl S1-211 Cl Cl C(Cl)═CHClS1-212 Cl Cl CH═CCl₂ S1-213 Cl Cl C(Cl)═CCl₂ S1-214 Cl Cl C(H)═CH(F)S1-215 Cl Cl C(H)═CF₂ S1-216 Cl Cl C(F)═CF₂ S1-217 Cl Cl C(F)═CHF S1-218Cl Cl CH═CHCH₂OH S1-219 Cl Cl CH═CHOCH₃ S1-220 Cl Cl CH═CHCH₂OCH₃ S1-221Cl Cl CH═CHCH₂OCF₃ S1-222 Cl Cl CH═CHCH₂OCCl₃ S1-223 Cl Cl CH═CH(C₃H₅)S1-224 Cl Cl CH═CH(C₄H₇) S1-225 Cl Cl CH═CH(1-Cl—C₃H₄) S1-226 Cl ClCH═CH(1-F—C₃H₄) S1-227 Cl Cl CH═CH(1-Cl—C₄H₆) S1-228 Cl ClCH═CH(1-F—C₄H₆) S1-229 Cl Cl C≡CH S1-230 Cl Cl C≡CCH₃ S1-231 Cl ClCH₂C≡CCH₃ S1-232 Cl Cl CH₂C≡CH S1-233 Cl Cl CH₂C≡CCH₂CH₃ S1-234 Cl ClC≡CCH(CH₃)₂ S1-235 Cl Cl C≡CC(CH₃)₃ S1-236 Cl Cl C≡C(C₃H₅) S1-237 Cl ClC≡C(C₄H₇) S1-238 Cl Cl C≡C(1-Cl—C₃H₄) S1-239 Cl Cl C≡C(1-Cl—C₄H₆) S1-240Cl Cl C≡CCl S1-241 Cl Cl C≡CBr S1-242 Cl Cl C≡C—I S1-243 Cl Cl CH₂C≡CClS1-244 Cl Cl CH₂C≡CBr S1-245 Cl Cl CH₂C≡C—I S1-246 Cl Cl C≡CCH₂OCH₃S1-247 Cl Cl C≡CCH(OH)CH₃ S1-248 Cl Cl C≡CCH(OCH₃)CH₃ S1-249 Cl ClC≡COCH₃ S1-250 Cl Cl CH₂C≡COCH₃ S1-251 Cl Cl C≡CCH₂OCCl₃ S1-252 Cl ClC≡CCH₂OCF₃ S1-253 Cl Cl C≡CCH₂(C₃H₅) S1-254 Cl Cl C≡CCH₂(C₄H₇) S1-255 ClCl C≡C(1-Cl—C₃H₄) S1-256 Cl Cl C≡C(1-F—C₃H₄) S1-257 Cl Cl C≡C(1-Cl—C₄H₆)S1-258 Cl Cl C≡C(1-F—C₄H₆) S1-259 Cl Cl C₃H₅ (cyclopropyl) S1-260 Cl ClC₄H₇ (cyclobutyl) S1-261 Cl Cl C₅H₉ (cyclopentyl) S1-262 Cl Clcyclohexyl S1-263 Cl Cl CH(CH₃)—C₃H₅ (CH(CH₃)-cyclopropyl) S1-264 Cl ClCH₂—C₃H₅ (CH₂-cyclopropyl) S1-265 Cl Cl 1-(Cl)-cyclopropyl S1-266 Cl Cl1-(F)-cyclopropyl S1-267 Cl Cl 1-(CH₃)-cyclopropyl S1-268 Cl Cl1-(CN)-cyclopropyl S1-269 Cl Cl 2-(Cl)-cyclopropyl S1-270 Cl Cl2-(F)-cyclopropyl S1-271 Cl Cl 1-(Cl)-cyclobutyl S1-272 Cl Cl1-(F)-cyclobutyl S1-273 Cl Cl 2-(Cl)-cyclobutyl S1-274 Cl Cl3-(Cl)-cyclobutyl S1-275 Cl Cl 2-(F)-cyclobutyl S1-276 Cl Cl3-(F)-cyclobutyl S1-277 Cl Cl 3,3-Cl₂-cyclobutyl S1-278 Cl Cl3,3-F₂-cyclobutyl S1-279 Cl Cl 2-(CH₃)-cyclopropyl S1-280 Cl Cl1-(CH₃)-cyclobutyl S1-281 Cl Cl 2-(CH₃)-cyclobutyl S1-282 Cl Cl3-(CH₃)-cyclobutyl S1-283 Cl Cl 3,3-(CH₃)₂-cyclobutyl S1-284 Cl Cl2-(CN)-cyclopropyl S1-285 Cl Cl 1-cyclopropyl-cyclopropyl S1-286 Cl Cl2-cyclopropyl-cyclopropyl S1-287 Cl Cl CH(CH₃)(cyclobutyl) S1-288 Cl ClCH₂-(cyclobutyl) S1-289 Cl Cl CH₂CH₂-(cyclopropyl) S1-290 Cl ClCH₂CH₂-(cyclobutyl) S1-291 Cl Cl CH₂-(1-Cl-cyclopropyl) S1-292 Cl ClCH₂-(1-F-cyclopropyl) S1-293 Cl Cl CH₂-(1-Cl-cyclobutyl) S1-294 Cl ClCH₂-(1-F-cyclobutyl) S1-295 Cl Cl CHCH₃-(1-Cl-cyclopropyl) S1-296 Cl ClC(CH₃)₂-(1-F-cyclopropyl) S1-297 Cl Cl C₆H₅ S1-298 Cl Cl 4-Cl—C₆H₄S1-299 Cl Cl 4-OCH₃—C₆H₄ S1-300 Cl Cl 4-CH₃—C₆H₄ S1-301 Cl Cl 4-F—C₆H₄S1-302 Cl Cl 2,4-F₂—C₆H₃ S1-303 Cl Cl 2,4-Cl₂—C₆H₃ S1-304 Cl Cl2-CH₃—C₆H₄ S1-305 Cl Cl 2-CF₃—C₆H₄ S1-306 Cl Cl 4-CH₃—C₆H₄ S1-307 Cl Cl4-CF₃—C₆H₄ S1-308 Cl Cl 2-OCH₃—C₆H₄ S1-309 Cl Cl 2-OCF₃—C₆H₄ S1-310 ClCl 4-OCH₃—C₆H₄ S1-311 Cl Cl 4-OCF₃—C₆H₄ S1-312 Cl Cl 2,4,6-F₃—C₆H₂S1-313 Cl Cl 2,4,6-Cl₃—C₆H₂ S1-314 Cl Cl CH₂C₆H₅ S1-315 Cl ClCH₂—(4-Cl)—C₆H₄ S1-316 Cl Cl CH₂—(4-CH₃)—C₆H₄ S1-317 Cl ClCH₂—(4-OCH₃)—C₆H₄ S1-318 Cl Cl CH₂—(4-F)—C₆H₄ S1-319 Cl ClCH₂—(2,4-Cl₂)—C₆H₃ S1-320 Cl Cl CH₂—(2,4-F₂)—C₆H₃

According the reaction conditions of the invention, it is possible toreduce the amount of I″ in favor of the desired product I. Consequently,according to the inventive process, it is possible to highly improve theyield of the triazole I compared to common prior art processes.

Furthermore, it has been found that if the reaction product I resultingfrom step (ii) is crystallized as described according to the invention,the product can be obtained in high yields and purity.

Consequently, according to one preferred embodiment of the invention,the compounds I resulting from step (ii) are crystallized from asuitable solvent such as, for example toluene, an aliphatic alcohol,acetonitrile, ethyl acetate and/or cyclohexane, in particular tolueneand/or an aliphatic alcohol.

In particular, the aliphatic alcohol is selected from methanol, ethanol,n-propanol, iso-propanol, n-butanol, isobutanol or any mixture thereof.In particular, the aliphatic alcohol is selected from methanol andethanol.

Generally, for the crystallizing step, the solvent, in particulardimethylformide as described above, is firstly evaporated in large part,preferably under reduced pressure. Preferably, at least 55% of thesolvent, more preferably at least 60% of the solvent, more specificallyat least 70% of the solvent are removed. Specifically, it may bepreferred, if at least 80%, more specifically at least 90% of thesolvent, such as DMF, are removed The solvent can then be recycled to beused again in the process step (ii), if necessary after it has beenfurther rectificated before.

Then, water and the respective suitable solvent such as an ether, forexample diethylether, diisopropylether, methyl-tert-butylether (MTBE),methylenechlorid and/or tolulene, in particular toluene, are added. Alsoethyl acetate can be appropriate as solvent. The product I is thenpreferably obtained by crystallization directly from the concentrated,e.g. toluene-reaction mixture. Also preferred and suitable according tothe invention is the change of solvent to e.g. methanol or ethanol (seeabove) for the crystallization of the products.

According to one embodiment, seed crystals are added for thecrystallization step.

By using the inventive crystallizing step according to the inventiveprocess, in particular when carrying out the process steps (ii) theformation of the undesired symmetric triazole I″ can be reduced to equalor less than 10%, more preferably equal or less than 8%, even morepreferably equal or less than 5%, even more preferably equal or lessthan 2%.

Preferably, the ratio of isolated compound I to I″ is at least 20:1,more preferably at least 30:1, even more preferably 50:1, morespecifically 70:1. In particular, the ratio of compound I to I″ is atleast 30:1.

Following the inventive process comprising step (i), also common methodsof further reacting the oxiranes II to end products I can be carriedout.

For example, the epoxide ring of compounds II may be cleaved by reactionwith alcohols R²OH preferably under acidic conditions to result incompounds V:

Thereafter, the resulting compounds V are reacted with halogenatingagents or sulfonating agents such as PBr₃, PCl₃ mesyl chloride, tosylchloride or thionyl chloride, to obtain compounds VI wherein LG′ is anucleophilically replaceable leaving group such as halogen,alkylsulfonyl, alkylsulfonyloxy and arylsulfonyloxy, preferably chloro,bromo or iodo, particularly preferably bromo or alkylsulfonyl. Thencompounds VI are reacted with 1H-1,2,4-triazole to obtain compounds I asknown in the art and/or described above:

For obtaining compounds of formula I, wherein the alcohol group isderivatized into an ether group to result in compounds of formula I-1,

wherein the variables R¹, R³, R⁴, n and m are defined and preferablydefined herein, and wherein

-   R² is hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, phenyl,    phenyl-C₁-C₄-alkyl, phenyl-C₂-C₄-alkenyl or phenyl-C₂-C₄-alkynyl;

wherein the aliphatic moieties of R² are not further substituted or docarry one, two, three or up to the maximum possible number of identicalor different groups R^(12a) which independently are selected from:

-   -   R^(12a) halogen, OH, CN, nitro, C₁-C₄-alkoxy, C₃-C₈-cycloalkyl,        C₃-C₈-halocycloalkyl and C₁-C₄-halogenalkoxy;

wherein the cycloalkyl and/or phenyl moieties of R² are not furthersubstituted or do carry one, two, three, four, five or up to the maximumnumber of identical or different groups R^(12b) which independently areselected from:

-   -   R^(12b) halogen, OH, CN, nitro, C₁-C₄-alkyl, C₁-C₄-alkoxy,        C₁-C₄-halogenalkyl, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl and        C₁-C₄-halogenalkoxy;

the following step can be carried out:

-   (iii) derivatizing the compound of formula I from step (i) under    basic conditions with R²-LG, wherein LG is a nucleophilically    replaceable leaving group;

LG represents a nucleophilically replaceable leaving group such ashalogen, alkylsulfonyl, alkylsulfonyloxy and arylsulfonyloxy, preferablychloro, bromo or iodo, particularly preferably bromo. Preferably a baseis ues in step (iii) such as for example, NaH.

Suitable solvents are for example ethers, in particular cyclic ethers.Possible solvents are for example tetrahydrofuran (THF),2-methyl-tetrahydrofuran (2-Me-THF), diethyl ether, TBME (tert-butylmethyl ether), CPME (cyclopentyl methyl ether), DME(1,2-dimethoxyethane) and 1,4-di-oxane. Further solvents that may besuitable are, for example, diisopropyl ether, di-n-butyl ether and/ordiglyme. Often, the use of THF or 2-methyl-THF is particularly suitable.Furthermore, it may also be suitable to use combinations of two or moredifferent solvents, such as for example any combination of the solventslisted above or any one of the listed ethers with aliphatic hydrocarbonslike n-hexane, heptane or aromatic hydrocarbons like toluene or xylenes.

The skilled person is familiar with the reaction in step (iii) and mayvary the reaction conditions analogously to known syntheses.

According to a further aspect the invention relates to a process for thepreparation of a triazole compound of the formula I

comprising the following step:

-   (iia) reacting an oxirane of the formula II as defined herein;    -   with 1H-1,2,4-triazole and an inorganic base, wherein less than        1 equivalent of said base is used per 1 equivalent of compound        II, resulting in compounds of formula I.

For obtaining compounds of formula I, wherein the alcohol group isderivatized (resulting in “OR²”, compounds I-1, see above), thefollowing step can be subsequently carried out:

-   (iiia) derivatizing the compound of formula I from step (iia) under    basic conditions with R²-LG, wherein LG is a nucleophilically    replaceable leaving group;

wherein the variables R¹, R³, R⁴, n and m are defined and preferablydefined herein.

The reaction steps (ii) and (iii) are described in detail above and alsoapply accordingly to this aspect of the invention, namely to thecorresponding steps (iia) and (iiia), with the proviso, that it ischaracteristic here that the inorganic base is used in an amount of lessthan 1 equivalent of per 1 equivalent of compound II.

The oxirane II used in this inventive process can be prepared accordingto the inventive process described above or may be also provided inanalogy to known processes, e.g. by reaction of the respectiveoxo-group-containing compound III with trimethylsulf(ox)onium halides((CH₃)₃S⁺ OHal⁻), preferably trimethylsulfoniumiodide, preferably in thepresence of a base such as sodium hydroxide (see also JACS 1965 87 p.1353).

The starting oxo-group containing compounds III for the inventiveprocesses can be synthesized as described in the above mentionedliterature and patent applications. Generally, the skilled person mayobtained by various routes in analogy to prior art processes known (cf.J. Agric. Food Chem. (2009) 57, 4854-4860; EP 0 275 955 A1; DE 40 03 180A1; EP 0 113 640 A2; EP 0 126 430 A2). In the following, synthesisroutes for obtaining the precursors are given.

In a first process, for example, phenoles A are reacted, in a firststep, with derivatives B, wherein X¹ stands for I or Br, in particularBr (=bromo derivatives III), preferably in the presence of a base toresult in compounds C.

Thereafter, the resulting compounds C, in particular X¹ is Br, are thentransformed into Grignard reagents by the reaction with transmetallationreagents such as isopropylmagnesium halides and subsequently reactedwith acetyl chloride preferably under anhydrous conditions andpreferably in the presence of a catalyst such as CuCl, CuCl₂, AlCl₃,LiCl and mixtures thereof, to obtain acetophenones D.

In a second process to obtain the precursors is as follows In a firststep, a halo derivative E, wherein X² is halogen, in particular F, andX³ is halogen, in particular Br, is reacted with a transmetallationagent such as e.g. isopropylmagnesium bromide followed by an acylchloride agent R¹COCl (e.g. acetyl chloride) preferably under anhydrousconditions and optionally in the presence of a catalyst such as CuCl,CuCl₂, AlCl₃, LiCl and mixtures thereof, to obtain ketones F.

Thereafter, ketones F are reacted with phenoles A preferably in thepresence of a base to obtain compounds III wherein R¹ is as defined andpreferably defined, respectively, herein.

Compounds III may also be obtained in analogy to the first processdescribed for compounds D (preferred conditions for the process step,see above). This is illustrated in the following:

Alternatively, compounds III can be synthesized via a Friedel Craftsacylation as follows:

Ethers H can be synthesized by nucleophilic substitution of X group incompound G (Angewandte Chemie, International Edition, 45(35), 5803-5807;2006, US 20070088015 A1, Journal of the American Chemical Society,134(17), 7384-7391; 2012). Then, a Lewis acid catalyzed addition of anacid halide, preferably will lead to compounds III (Journal of ChemicalResearch, Synopses, (8), 245; 1992, WO2010096777 A1).

If individual compounds cannot be directly obtained by the routesdescribed above, they can be prepared by derivatization of othercompounds.

In case a work-up of the reaction mixture in any of the reaction stepsof the inventive process or the other processes described, is suitable,it can be carried out by procedures known in a general manner to theperson skilled in the art. Usually, the reaction mixture is extractedwith a suitable organic solvent (for example aromatic hydrocarbons suchas toluene and xylenes) and the residue is, if appropriate, purified byrecrystallization and/or chromatography.

In the definitions of the variables given herein, collective terms areused which are generally representative for the substituents inquestion. The term “C_(n)-C_(m)” indicates the number of carbon atomspossible in each case in the substituent or substituent moiety inquestion.

The term “halogen” refers to fluorine, chlorine, bromine and iodine.

The term “C₁-C₆-alkyl” refers to a straight-chained or branchedsaturated hydrocarbon group having 1 to 6 carbon atoms, e.g. methyl,ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl,1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethyl-butyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and1-ethyl-2-methylpropyl. Likewise, the term “C₂-C₄-alkyl” refers to astraight-chained or branched alkyl group having 2 to 4 carbon atoms,such as ethyl, propyl (n-propyl), 1-methylethyl (iso-propoyl), butyl,1-methylpropyl (sec.-butyl), 2-methylpropyl (iso-butyl),1,1-dimethylethyl (tert.-butyl).

The term “C₁-C₆-haloalkyl” refers to an alkyl group having 1 or 6 carbonatoms as defined above, wherein some or all of the hydrogen atoms inthese groups may be replaced by halogen atoms as mentioned above.Examples are “C₁-C₂-haloalkyl” groups such as chloromethyl, bromomethyl,dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, chloro-fluoromethyl, dichlorofluoromethyl,chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl,2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl,2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl.

The term “C₂-C₆-alkenyl” refers to a straight-chain or branchedunsaturated hydrocarbon radical having 2 to 6 carbon atoms and a doublebond in any position. Examples are “C₂-C₄-alkenyl” groups, such asethenyl, 1-propenyl, 2-propenyl (allyl), 1-methylethenyl, 1-butenyl,2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl,1-methyl-2-propenyl, 2-methyl-2-propenyl.

The term “C₂-C₆-alkynyl” refers to a straight-chain or branchedunsaturated hydrocarbon radical having 2 to 6 carbon atoms andcontaining at least one triple bond. Examples are “C₂-C₄-alkynyl”groups, such as ethynyl, prop-1-ynyl, prop-2-ynyl (propargyl),but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-2-ynyl.

The term “C₃-C₈-cycloalkyl” refers to monocyclic saturated hydrocarbonradicals having 3 to 8 carbon ring members, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

The term “C₃-C₈-cycloalkyl-C₁-C₄-alkyl” refers to alkyl having 1 to 4carbon atoms (as defined above), wherein one hydrogen atom of the alkylradical is replaced by a cycloalkyl radical having 3 to 8 carbon atoms(as defined above).

The term “C₁-C₆-alkoxy” refers to a straight-chain or branched alkylgroup having 1 to 6 carbon atoms which is bonded via an oxygen, at anyposition in the alkyl group. Examples are “C₁-C₄-alkoxy” groups, such asmethoxy, ethoxy, n-propoxy, 1-methylethoxy, butoxy, 1-methyl-propoxy,2-methylpropoxy or 1,1-dimethylethoxy.

The term “C₁-C₆-haloalkoxy” refers to a C₁-C₆-alkoxy radical as definedabove, wherein some or all of the hydrogen atoms in these groups may bereplaced by halogen atoms as mentioned above. Examples are“C₁-C₄-haloalkoxy” groups, such as OCH₂F, OCHF₂, OCF₃, OCH₂Cl, OCHCl₂,OCCl₃, chlorofluoromethoxy, dichlorofluoromethoxy,chlorodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy,2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy,2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy,2,2-dichloro-2-fluoroethoxy, 2,2,2-tri-chloro¬ethoxy, OC₂F₅,2-fluoropropoxy, 3-fluoropropoxy, 2,2-difluoropropoxy,2,3-difluoro¬propoxy, 2 chloropropoxy, 3-chloropropoxy,2,3-dichloropropoxy, 2-bromo¬propoxy, 3 bromopropoxy,3,3,3-trifluoropropoxy, 3,3,3-trichloropropoxy, OCH₂—C₂F₅, OCF₂—C₂F₅,1-fluoromethyl-2-fluoroethoxy, 1-chloromethyl-2-chloroethoxy,1-bromomethyl-2-bromo¬ethoxy, 4-fluorobutoxy, 4-chlorobutoxy,4-bromobutoxy or nonafluorobutoxy.

The term “phenyl-C₁-C₆-alkyl” refers to alkyl having 1 to 6 carbon atoms(as defined above), wherein one hydrogen atom of the alkyl radical isreplaced by a phenyl radical. Likewise, the terms “phenyl-C₂-C₆-alkenyl”and “phenyl-C₂-C₆-alkynyl” refer to alkenyl and alkynyl, respectively,wherein one hydrogen atom of the aforementioned radicals is replaced bya phenyl radical.

The meanings and preferred meanings described in the following for thevariables R¹, R², R³, R⁴, n and m apply to compounds and the precursorsof the compounds I and side products in any of the above detailedinventive processes.

R¹ according to the present invention is hydrogen, C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₈-cycloalkyl,C₃-C₈-cycloalkyl-C₁-C₆-alkyl, phenyl, phenyl-C₁-C₄-alkyl,phenyl-C₂-C₄-alkenyl or phenyl-C₂-C₄-alkynyl, wherein the aliphaticmoieties of R¹ may carry one, two, three or up to the maximum possiblenumber of identical or different groups R^(12a) which independently ofone another are selected from halogen, OH, CN, nitro, C₁-C₄-alkoxy,C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl and C₁-C₄-halogenalkoxy; andwherein the cycloalkyl and/or phenyl moieties of R¹ may carry one, two,three, four, five or up to the maximum number of identical or differentgroups R^(12b), which independently of one another are selected fromhalogen, OH, CN, nitro, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-halogenalkyl,C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl and C₁-C₄-halogenalkoxy.

According to one embodiment, R¹ is H.

According to a further embodiment of the invention, R¹ is selected fromC₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₈-cycloalkyl,C₃-C₈-cycloalkyl-C₁-C₄-alkyl, phenyl, phenyl-C₁-C₄-alkyl,phenyl-C₂-C₄-alkenyl and phenyl-C₂-C₄-alkynyl, wherein the R¹ are ineach case unsubstituted or are substituted by R^(12a) and/or R^(12b) asdefined and preferably defined herein. Specific embodiments thereof canbe found in the below Table P1.

According to one particular embodiment, R¹ is C₁-C₆-alkyl, in particularC₁-C₄-alkyl, such as CH₃, C₂H₅, CH(CH₃)₂ or C(CH₃)₃. A furtherembodiment relates to compounds, wherein R¹ is C₁-C₆-alkyl, inparticular C₁-C₄-alkyl, that is substituted by one, two or three or upto the maximum possible number of identical or different groups R^(12a),as defined and preferably defined herein. According to a specificembodiment thereof, R¹ is C₁-C₆-haloalkyl, in particularC₁-C₄-haloalkyl, more particularly C₁-C₂-haloalkyl such as CF₃ or CHF₂.According to a further specific embodiment thereof, R¹ isC₁-C₄-alkoxy-C₁-C₆-alkyl, in particular C₁-C₄-alkoxy-C₁-C₄-alkyl, suchas CH₂—OCH₃. Further specific embodiments thereof can be found in thebelow Table P1.

According to still another embodiment, R¹ isC₃-C₈-cycloalkyl-C₁-C₆-alkyl, in particularC₃-C₆-cycloalkyl-C₁-C₄-alkyl. A further embodiment relates to compounds,wherein R¹ is C₃-C₈-cycloalkyl-C₁-C₆-alkyl, in particularC₃-C₆-cycloalkyl-C₁-C₄-alkyl, that is substituted by one, two or threeor up to the maximum possible number of identical or different groupsR^(12a) in the alkyl moiety and/or substituted by one, two, three fouror five or up to the maximum possible number of identical or differentgroups R^(12b) in the cycloalkyl moiety. R^(12a) and R^(12b) are in eachcase as defined and preferably defined herein. Specific embodimentsthereof can be found in the below Table P1.

According to another embodiment, R¹ is C₂-C₆-alkenyl, in particularC₂-C₄-alkenyl, such as CH═CH₂, CH₂CH═CH₂, CH═CHCH₃ or C(CH₃)═CH₂. Afurther embodiment relates to compounds, wherein R¹ is C₂-C₆-alkenyl, inparticular C₂-C₄-alkenyl, that is substituted by one, two or three or upto the maximum possible number of identical or different groups R^(12a)as defined and preferably defined herein. According to a specificembodiment thereof, R¹ is C₂-C₆-haloalkenyl, in particularC₂-C₄-haloalkenyl. According to a further specific embodiment thereof,R¹ is C₃-C₈-cycloalkyl-C₂-C₆-alkenyl orC₃-C₈-halocycloalkyl-C₂-C₆-alkenyl, in particularC₃-C₆-cycloalkyl-C₂-C₄-alkenyl or C₃-C₆-halocycloalkyl-C₂-C₄-alkenyl.Further specific embodiments thereof can be found in the below Table P1.

According to still another embodiment, R¹ is C₂-C₆-alkynyl, inparticular C₂-C₄-alkynyl, such as C≡CH, C≡CCH₃, CH₂—C≡C—H orCH₂—C≡C—CH₃. A further embodiment relates to compounds, wherein R¹ isC₂-C₆-alkynyl, in particular C₂-C₄-alkynyl, that is substituted by one,two or three or up to the maximum possible number of identical ordifferent groups R^(12a), as defined and preferably defined herein.According to a specific embodiment thereof, R¹ is C₂-C₆-haloalkynyl, inparticular C₂-C₄-haloalkynyl. According to a further specific embodimentthereof, R¹ is C₃-C₈-cycloalkyl-C₂-C₆-alkynyl orC₃-C₅-halocycloalkyl-C₂-C₆-alkynyl, in particularC₃-C₆-cycloalkyl-C₂-C₄-alkynyl or C₃-C₆-halocycloalkyl-C₂-C₄-alkynyl.Further specific embodiments thereof can be found in the below Table P1.

According to still another embodiment, R¹ is phenyl-C₁-C₄-alkyl, inparticular phenyl-C₁-C₂-alkyl, such as benzyl, wherein the alkyl moietyin each case is unsubstituted or carries one, two or three R^(12a) asdefined and preferably defined herein, in particular selected fromhalogen, in particular F and Cl, C₁-C₄-alkoxy, in particular OCH₃, andCN, and wherein the phenyl in each case is unsubstituted or carries one,two or three R^(12b) as defined and preferably defined herein, inparticular selected from halogen, in particular Cl and F, C₁-C₄-alkoxy,in particular OCH₃, C₁-C₄-alkyl, in particular CH₃ or C₂H₅, and CN.Specific embodiments thereof can be found in the below Table P1.

According to still another embodiment, R¹ is phenyl-C₂-C₄-alkenyl, inparticular phenyl-C₂-C₃-alkenyl, such as phenylethenyl, wherein thealkenyl moiety in each case is unsubstituted or carries one, two orthree R^(12a) as defined and preferably defined herein, in particularselected from halogen, in particular F and Cl, C₁-C₄-alkoxy, inparticular OCH₃, and CN, and wherein the phenyl in each case isunsubstituted or carries one, two or three R^(12b) as defined andpreferably defined herein, in particular selected from halogen, inparticular Cl and F, C₁-C₄-alkoxy, in particular OCH₃, C₁-C₄-alkyl, inparticular CH₃ or C₂H₅, and CN. According to still another embodiment,R¹ is phenyl-C₂-C₄-alkynyl, in particular phenyl-C₂-C₃-alkynyl, such asphenylethinyl, wherein the alkynyl moiety in each case is unsubstitutedor carries one, two or three R^(12a), as defined and preferably definedherein, in particular selected from halogen, in particular F and Cl,C₁-C₄-alkoxy, in particular OCH₃, and CN, and wherein the phenyl in eachcase is unsubstituted or carries one, two or three R^(12b) as definedand preferably defined herein, in particular selected from halogen, inparticular Cl and F, C₁-C₄-alkoxy, in particular OCH₃, C₁-C₄-alkyl, inparticular CH₃ or C₂H₅, and CN. Specific embodiments thereof can befound in the below Table P1.

According to still another embodiment, R¹ is C₃-C₈-cycloalkyl, inparticular C₃-C₆-cycloalkyl, such as C₃H₅ (cyclopropyl), C₄H₇(cyclobutyl), cyclopentyl or cyclohexyl. A further embodiment relates tocompounds, wherein R¹ is C₃-C₈-cycloalkyl, in particularC₃-C₆-cycloalkyl, such as C₃H₅ (cyclopropyl) or C₄H₇ (cyclobutyl), thatis substituted by one, two, three four or five or up to the maximumpossible number of identical or different groups R^(12b) as defined andpreferably defined herein. According to a specific embodiment thereof,R¹ is C₃-C₈-halocycloalkyl, in particular C₃-C₆-halocycloalkyl, such ashalocyclopropyl, in particular 1-F-cyclopropyl or 1-Cl-cyclopropyl.According to a further specific embodiment thereof, R¹ isC₃-C₈-cycloalkyl-C₃-C₈-cycloalkyl, in particularC₃-C₆-cycloalkyl-C₃-C₆-cycloalkyl, wherein each of saidcycloalkyl-cycloalkyl moieties is unsubstituted or carries one, two orthree R^(12b) as defined and preferably defined herein, such as1-cyclopropyl-cyclopropyl or 2-cyclopropyl-cyclopropyl. Specificembodiments thereof can be found in the below Table P1.

According to still another embodiment, R¹ is phenyl, wherein the phenylis unsubstituted or carries one, two, three, four or five independentlyselected R^(12b) as defined and preferably defined herein, in particularselected from halogen, in particular Cl and F, C₁-C₄-alkoxy, inparticular OCH₃, C₁-C₄-alkyl, in particular CH₃ or C₂H₅, and CN.Specific embodiments thereof can be found in the below Table P1.

In a further embodiment of the invention, R¹ is selected from hydrogen,C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl and C₃-C₆-cycloalkyl, whereinthe R¹ are in each case unsubstituted or are substituted by R^(12a)and/or R^(12b) as defined and preferably defined herein. In each case,the substituents may also have the preferred meanings for the respectivesubstituent as defined above. Specific embodiments thereof can be foundin the below Table P1.

Particularly preferred embodiments of R¹ according to the invention arein Table P1 below, wherein each line of lines P1-1 to P1-160 correspondsto one particular embodiment of the invention, wherein P1-1 to P1-160are also in any combination a preferred embodiment of the presentinvention.

TABLE P1 line R¹ P1-1 H P1-2 CH₃ P1-3 CH₂CH₃ P1-4 CH₂CH₂CH₃ P1-5CH(CH₃)₂ P1-6 C(CH₃)₃ P1-7 CH(CH₃)CH₂CH₃ P1-8 CH₂CH(CH₃)₂ P1-9CH₂CH₂CH₂CH₃ P1-10 CF₃ P1-11 CHF₂ P1-12 CH₂F P1-13 CHCl₂ P1-14 CH₂ClP1-15 CH₂OH P1-16 CH₂CH₂OH P1-17 CH₂CH₂CH₂OH P1-18 CH(CH₃)CH₂OH P1-19CH₂CH(CH₃)OH P1-20 CH₂CH₂CH₂CH₂OH P1-21 CH(CH₃)CN P1-22 CH₂CH₂CN P1-23CH₂CN P1-24 CH₂CH₂CN P1-25 CH₂CH₂CH₂CN, P1-26 CH(CH₃)CH₂CN P1-27CH₂CH(CH₃)CN P1-28 CH₂CH₂CH₂CH₂CN P1-29 CH₂OCH₃ P1-30 CH₂OCH₂CH₃ P1-31CH(CH₃)OCH₃ P1-32 CH(CH₃)OCH₂CH₃ P1-33 CH₂CH₂OCH₂CH₃ P1-34 CH₂OCF₃ P1-35CH₂CH₂OCF₃ P1-36 CH₂OCCl₃ P1-37 CH₂CH₂OCCl₃ P1-38 CH═CH₂ P1-39 CH₂CH═CH₂P1-40 CH₂CH═CHCH₃ P1-41 CH₂C(CH₃)═CH₂ P1-42 CH₂C(CH₃)═CHCH₃ P1-43CH₂C(CH₃)═C(CH₃)₂ P1-44 CH═CHCH₃ P1-45 C(CH₃)═CH₂ P1-46 CH═C(CH₃)₂ P1-47C(CH₃)═C(CH₃)₂ P1-48 C(CH₃)═CH(CH₃) P1-49 C(Cl)═CH₂ P1-50 C(H)═CHClP1-51 C(Cl)═CHCl P1-52 CH═CCl₂ P1-53 C(Cl)═CCl₂ P1-54 C(H)═CH(F) P1-55C(H)═CF₂ P1-56 C(F)═CF₂ P1-57 C(F)═CHF P1-58 CH═CHCH₂OH P1-59 CH═CHOCH₃P1-60 CH═CHCH₂OCH₃ P1-61 CH═CHCH₂OCF₃ P1-62 CH═CHCH₂OCCl₃ P1-63CH═CH(C₃H₅) P1-64 CH═CH(C₄H₇) P1-65 CH═CH(1-Cl—C₃H₄) P1-66CH═CH(1-F—C₃H₄) P1-67 CH═CH(1-Cl—C₄H₆) P1-68 CH═CH(1-F—C₄H₆) P1-69 C≡CHP1-70 C≡CCH₃ P1-71 CH₂C≡CCH₃ P1-72 CH₂C≡CH P1-73 CH₂C≡CCH₂CH₃ P1-74C≡CCH(CH₃)₂ P1-75 C≡CC(CH₃)₃ P1-76 C≡C(C₃H₅) P1-77 C≡C(C₄H₇) P1-78C≡C(1-Cl—C₃H₄) P1-79 C≡C(1-Cl—C₄H₆) P1-80 C≡CCl P1-81 C≡CBr P1-82 C≡C—IP1-83 CH₂C≡CCl P1-84 CH₂C≡CBr P1-85 CH₂C≡C—I P1-86 C≡CCH₂OCH₃ P1-87C≡CCH(OH)CH₃ P1-88 C≡CCH(OCH₃)CH₃ P1-89 C≡COCH₃ P1-90 CH₂C≡COCH₃ P1-91C≡CCH₂OCCl₃ P1-92 C≡CCH₂OCF₃ P1-93 C≡CCH₂(C₃H₅) P1-94 C≡CCH₂(C₄H₇) P1-95C≡C(1-Cl—C₃H₄) P1-96 C≡C(1-F—C₃H₄) P1-97 C≡C(1-Cl—C₄H₆) P1-98C≡C(1-F—C₄H₆) P1-99 C₃H₅ (cyclopropyl) P1-100 C₄H₇ (cyclobutyl) P1-101C₅H₉ (cyclopentyl) P1-102 cyclohexyl P1-103 CH(CH₃)—C₃H₅(CH(CH₃)-cyclopropyl) P1-104 CH₂—C₃H₅ (CH₂-cyclopropyl) P1-1051-(Cl)-cyclopropyl P1-106 1-(F)-cyclopropyl P1-107 1-(CH₃)-cyclopropylP1-108 1-(CN)-cyclopropyl P1-109 2-(Cl)-cyclopropyl P1-1102-(F)-cyclopropyl P1-111 1-(Cl)-cyclobutyl P1-112 1-(F)-cyclobutylP1-113 2-(Cl)-cyclobutyl P1-114 3-(Cl)-cyclobutyl P1-1152-(F)-cyclobutyl P1-116 3-(F)-cyclobutyl P1-117 3,3-Cl₂-cyclobutylP1-118 3,3-F₂-cyclobutyl P1-119 2-(CH₃)-cyclopropyl P1-1201-(CH₃)-cyclobutyl P1-121 2-(CH₃)-cyclobutyl P1-122 3-(CH₃)-cyclobutylP1-123 3,3-(CH₃)₂-cyclobutyl P1-124 2-(CN)-cyclopropyl P1-1251-cyclopropyl-cyclopropyl P1-126 2-cyclopropyl-cyclopropyl P1-127CH(CH₃)(cyclobutyl) P1-128 CH₂-(cyclobutyl) P1-129 CH₂CH₂-(cyclopropyl)P1-130 CH₂CH₂-(cyclobutyl) P1-131 CH₂-(1-Cl-cyclopropyl) P1-132CH₂-(1-F-cyclopropyl) P1-133 CH₂-(1-Cl-cyclobutyl) P1-134CH₂-(1-F-cyclobutyl) P1-135 CHCH₃-(1-Cl-cyclopropyl) P1-136C(CH₃)₂-(1-F-cyclopropyl) P1-137 C₆H₅ P1-138 4-Cl—C₆H₄ P1-1394-OCH₃—C₆H₄ P1-140 4-CH₃—C₆H₄ P1-141 4-F—C₆H₄ P1-142 2,4-F₂—C₆H₃ P1-1432,4-Cl₂—C₆H₃ P1-144 2-CH₃—C₆H₄ P1-145 2-CF₃—C₆H₄ P1-146 4-CH₃—C₆H₄P1-147 4-CF₃—C₆H₄ P1-148 2-OCH₃—C₆H₄ P1-149 2-OCF₃—C₆H₄ P1-1504-OCH₃—C₆H₄ P1-151 4-OCF₃—C₆H₄ P1-152 2,4,6-F₃—C₆H₂ P1-1532,4,6-Cl₃—C₆H₂ P1-154 CH₂C₆H₅ P1-155 CH₂-(4-Cl)—C₆H₄ P1-156CH₂-(4-CH₃)—C₆H₄ P1-157 CH₂-(4-OCH₃)—C₆H₄ P1-158 CH₂-(4-F)—C₆H₄ P1-159CH₂-(2,4-Cl₂)—C₆H₃ P1-160 CH₂-(2,4-F₂)—C₆H₃

R² in compounds I-1 prepared according to the present invention or inprecursors thereof, is C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl, phenyl,phenyl-C₁-C₄-alkyl, phenyl-C₂-C₄-alkenyl or phenyl-C₂-C₄-alkynyl,wherein the aliphatic groups of R² may carry one, two, three or up tothe maximum possible number of identical or different groups R^(12a)which independently of one another are selected from halogen, OH, CN,nitro, C₁-C₄-alkoxy, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl andC₁-C₄-halogenalkoxy; and wherein the cycloalkyl and/or phenyl moietiesof R² may carry one, two, three, four, five or up to the maximum numberof identical or different groups R^(12b), which independently of oneanother are selected from halogen, OH, CN, nitro, C₁-C₄-alkyl,C₁-C₄-alkoxy, C₁-C₄-halogenalkyl, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyland C₁-C₄-halogenalkoxy.

According to a further embodiment of the invention, R² is selected fromC₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₈-cycloalkyl,C₃-C₈-cycloalkyl-C₁-C₄-alkyl, phenyl, phenyl-C₁-C₄-alkyl,phenyl-C₂-C₄-alkenyl and phenyl-C₂-C₄-alkynyl, wherein the R² are ineach case unsubstituted or are substituted by R^(12a) and/or R^(12b) asdefined and preferably defined herein. Specific embodiments thereof canbe found in the below Table P2.

According to one particular embodiment, R² is C₁-C₆-alkyl, in particularC₁-C₄-alkyl, such as CH₃, C₂H₅, CH(CH₃)₂, CH₂CH₂CH₃, CH₂CH₂CH₂CH₃,CH₂CH(CH₃)₂. A further embodiment relates to compounds, wherein R² isC₁-C₆-alkyl, in particular C₁-C₄-alkyl, that is substituted by one, twoor three or up to the maximum possible number of identical or differentgroups R^(12a), as defined and preferably defined herein. According to aspecific embodiment thereof, R² is C₁-C₆-haloalkyl, in particularC₁-C₄-haloalkyl, more particularly C₁-C₂-haloalkyl. According to afurther specific embodiment thereof, R² is C₁-C₄-alkoxy-C₁-C₆-alkyl, inparticular C₁-C₄-alkoxy-C₁-C₄-alkyl, such as CH₂OCH₃ or CH₂CH₂OCH₃.According to still a further specific embodiment thereof, R² ishydroxy-C₁-C₆-alkyl, in particular hydroxyl-C₁-C₄-alkyl, such asCH₂CH₂OH. Further specific embodiments thereof can be found in the belowTable P2

According to still another embodiment, R² isC₃-C₈-cycloalkyl-C₁-C₆-alkyl, in particularC₃-C₆-cycloalkyl-C₁-C₄-alkyl. A further embodiment relates to compounds,wherein R² is C₃-C₈-cycloalkyl-C₁-C₆-alkyl, in particularC₃-C₆-cycloalkyl-C₁-C₄-alkyl, more particularlyC₃-C₆-cycloalkyl-C₁-C₂-alkyl, that is substituted by one, two or threeor up to the maximum possible number of identical or different groupsR^(12a) in the alkyl moiety and/or substituted by one, two, three fouror five or up to the maximum possible number of identical or differentgroups R^(12b) in the cycloalkyl moiety. R^(12a) and R^(12b) are in eachcase as defined and preferably defined herein. Specific embodimentsthereof can be found in the below Table P2.

According to another embodiment, R² is C₂-C₆-alkenyl, in particularC₂-C₄-alkenyl, such as CH₂CH═CH₂, CH₂C(CH₃)═CH₂ or CH₂CH═CHCH₃. Afurther embodiment relates to compounds, wherein R² is C₂-C₆-alkenyl, inparticular C₂-C₄-alkenyl, that is substituted by one, two or three or upto the maximum possible number of identical or different groups R^(12a)as defined and preferably defined herein. According to a specificembodiment thereof, R² is C₂-C₆-haloalkenyl, in particularC₂-C₄-haloalkenyl, such as CH₂C(Cl)═CH₂ and CH₂C(H)═CHCl. According to afurther specific embodiment thereof, R² isC₃-C₈-cycloalkyl-C₂-C₆-alkenyl or C₃-C₈-halocycloalkyl-C₂-C₆-alkenyl, inparticular C₃-C₆-cycloalkyl-C₂-C₄-alkenyl orC₃-C₆-halocycloalkyl-C₂-C₄-alkenyl. Further specific embodiments thereofcan be found in the below Table P2.

According to still another embodiment, R² is C₂-C₆-alkynyl, inparticular C₂-C₄-alkynyl, such as CH₂C═CH or CH₂C═CCH₃. A furtherembodiment relates to compounds, wherein R² is C₂-C₆-alkynyl, inparticular C₂-C₄-alkynyl, that is substituted by one, two or three or upto the maximum possible number of identical or different groups R^(12a),as defined and preferably defined herein. According to a specificembodiment thereof, R² is C₂-C₆-haloalkynyl, in particularC₂-C₄-haloalkynyl. According to a further specific embodiment thereof,R² is C₃-C₈-cycloalkyl-C₂-C₆-alkynyl orC₃-C₈-halocycloalkyl-C₂-C₆-alkynyl, in particularC₃-C₆-cycloalkyl-C₂-C₄-alkynyl or C₃-C₆-halocycloalkyl-C₂-C₄-alkynyl.Specific embodiments thereof can be found in the below Table P2.

According to still another embodiment, R² is phenyl-C₁-C₄-alkyl, inparticular phenyl-C₁-C₂-alkyl, such as benzyl, wherein the alkyl moietyin each case is unsubstituted or carries one, two or three R^(12a) asdefined and preferably defined herein, in particular selected fromhalogen, in particular F and Cl, C₁-C₄-alkoxy, in particular OCH₃, andCN, and wherein the phenyl in each case is unsubstituted or carries one,two or three R^(12b) as defined and preferably defined herein, inparticular selected from halogen, in particular Cl and F, C₁-C₄-alkoxy,in particular OCH₃, C₁-C₄-alkyl, in particular CH₃ or C₂H₅, and CN.Specific embodiments thereof can be found in the below Table P2.

According to still another embodiment, R² is phenyl-C₂-C₄-alkenyl, inparticular phenyl-C₂-C₃-alkenyl, such as phenylethenyl, wherein thealkenyl moiety in each case is unsubstituted or carries one, two orthree R^(12a) as defined and preferably defined herein, in particularselected from halogen, in particular F and Cl, C₁-C₄-alkoxy, inparticular OCH₃, and CN, and wherein the phenyl in each case isunsubstituted or carries one, two or three R^(12b) as defined andpreferably defined herein, in particular selected from halogen, inparticular Cl and F, C₁-C₄-alkoxy, in particular OCH₃, C₁-C₄-alkyl, inparticular CH₃ or C₂H₅, and CN.

According to still another embodiment, R² is phenyl-C₂-C₄-alkynyl, inparticular phenyl-C₂-C₃-alkynyl, such as phenylethinyl, wherein thealkynyl moiety in each case is unsubstituted or carries one, two orthree R^(12a), as defined and preferably defined herein, in particularselected from halogen, in particular F and Cl, C₁-C₄-alkoxy, inparticular OCH₃, and CN, and wherein the phenyl in each case isunsubstituted or carries one, two or three R^(12b) as defined andpreferably defined herein, in particular selected from halogen, inparticular Cl and F, C₁-C₄-alkoxy, in particular OCH₃, C₁-C₄-alkyl, inparticular CH₃ or C₂H₅, and CN.

According to still another embodiment, R² is C₃-C₈-cycloalkyl, inparticular C₃-C₆-cycloalkyl, such as C₃H₅ (cyclopropyl), C₄H₇(cyclobutyl), cyclopentyl or cyclohexyl. A further embodiment relates tocompounds, wherein R² is C₃-C₈-cycloalkyl, in particularC₃-C₆-cycloalkyl, such as C₃H₅ (cyclopropyl) or C₄H₇ (cyclobutyl), thatis substituted by one, two, three four or five or up to the maximumpossible number of identical or different groups R^(12b) as defined andpreferably defined herein. According to a specific embodiment thereof,R² is C₃-C₈-halocycloalkyl, in particular C₃-C₆-halocycloalkyl, such ashalocyclopropyl, in particular 1-F-cyclopropyl or 1-Cl-cyclopropyl.According to a further specific embodiment thereof, R² isC₃-C₈-cycloalkyl-C₃-C₈-cycloalkyl, in particularC₃-C₆-cycloalkyl-C₃-C₆-cycloalkyl, wherein each of saidcycloalkyl-cycloalkyl moieties is unsubstituted or carries one, two orthree R^(12b) as defined and preferably defined herein.

According to still another embodiment, R² is phenyl, wherein the phenylis unsubstituted or carries one, two, three, four or five independentlyselected R^(12b) as defined and preferably defined herein, in particularselected from halogen, in particular Cl and F, C₁-C₄-alkoxy, inparticular OCH₃, C₁-C₄-alkyl, in particular CH₃ or C₂H₅, and CN.

In a further embodiment of the invention, R² is selected fromC₁-C₆-alkyl, C₂-C₆-alkenyl and C₂-C₆-alkynyl, wherein the R² are in eachcase unsubstituted or are substituted by R^(12a) and/or R^(12b) asdefined and preferably defined herein. In each case, the substituentsmay also have the preferred meanings for the respective substituent asdefined above. Specific embodiments thereof can be found in the belowTable P2.

R^(12a) are the possible substituents for any aliphatic moiety of R¹and/or R² and can independently be defined for R¹ and R².

R^(12a) according to the invention is independently selected fromhalogen, CH, CN, nitro, C₁-C₄-alkoxy, C₃-C₈-cycloalkyl,C₃-C₈-halocycloalkyl and C₁-C₄-halogenalkoxy.

According to one embodiment R^(12a) is independently selected fromhalogen, CH, CN, C₁-C₂-alkoxy, C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyland C₁-C₂-halogenalkoxy. Specifically, R^(12a) is independently selectedfrom F, Cl, CH, CN, C₁-C₂-alkoxy, cyclopropyl, 1-F-cyclopropyl,1-Cl-cyclopropyl and C₁-C₂-halogenalkoxy.

R^(12b) are the possible substituents for any cycloalkyl and/or phenylmoiety of R¹ and/or R² and can independently be defined for R¹ and R².

R^(12b) according to the invention is independently selected fromhalogen, OH, CN, nitro, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-halogenalkyl,C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl and C₁-C₄-halogenalkoxy.

According to one embodiment R^(12b) is independently selected fromhalogen, CN, nitro, C₁-C₂-alkyl, C₁-C₂-alkoxy, C₁-C₂-halogenalkyl,C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl and C₁-C₂-halogenalkoxy.Specifically, R^(12b) is independently selected from F, Cl, OH, CN,nitro, CH₃, OCH₃, cyclopropyl, 1-F-cyclopropyl, 1-Cl-cyclopropyl andhalogenmethoxy.

Particularly preferred embodiments of R² according to the invention arein Table P2 below, wherein each line of lines P2-1 to P2-87 correspondsto one particular embodiment of the invention, wherein P2-1 to P2-87 arealso in any combination a preferred embodiment of the present invention.

TABLE P2 line R² P2-1 CH₃ P2-2 CH₂CH₃ P2-3 CH(CH₃)₂ P2-4 CH₂CH₂CH₃ P2-5CH₂CH₂CH₂CH₃ P2-6 CH₂CH(CH₃)₂ P2-7 CF₃. P2-8 CHF₂ P2-9 CFH₂ P2-10 CCl₃.P2-11 CHCl₂ P2-12 CClH₂ P2-13 CH₂CF₃ P2-14 CH₂CHF₂ P2-15 CH₂CCl₃ P2-16CH₂CHCl₂ P2-17 CH₂CH₂OCH₂CH₃ P2-18 CH(CH₃)OCH₂CH₃ P2-19 CH(CH₃)OCH₃P2-20 CH₂OCH₃ P2-21 CH₂CH₂OCH₃ P2-22 CH₂OCF₃ P2-23 CH₂CH₂OCF₃ P2-24CH₂OCCl₃ P2-25 CH₂CH₂OCCl₃ P2-26 CH₂CH₂OH P2-27 CH₂OH P2-28 CH₂CH₂CH₂OH,P2-29 CH(CH₃)CH₂OH P2-30 CH₂CH(CH₃)OH P2-31 CH₂CH₂CH₂CH₂OH P2-32 CH₂CN,P2-33 CH₂CH₂CN, P2-34 CH₂CH₂CH₂CN, P2-35 CH(CH₃)CH₂CN, P2-36CH₂CH(CH₃)CN, P2-37 CH₂CH₂CH₂CH₂CN P2-38 CH═CH₂ P2-39 C(CH₃)═CH₂ P2-40CH═CHCH₃ P2-41 CH₂CH═CH₂ P2-42 CH₂CH═CHCH₃ P2-43 CH₂C(CH₃)═CH₂ P2-44C(CH₃)═CH(CH₃) P2-45 C(CH₃)═C(CH₃)₂ P2-46 CH═C(CH₃)₂ P2-47 CH═C(Cl)₂P2-48 C(CH₃)═CH₂ P2-49 CH₂C(Cl)═CH₂ P2-50 CH₂C(H)═CHCl P2-51 CH═CHCH₂OHP2-52 CH═C(CH₃)OH P2-53 CH═CHOCH₃ P2-54 CH═CHCH₂OCH₃ P2-55CH₂CH═CHCH₂OCH₃ P2-56 CH═CHOCF₃ P2-57 CH═CHCH₂OCF₃ P2-58 CH═CHOCCl₃P2-59 CH═CHCH₂OCCl₃ P2-60 CH₂CH═CH(C₃H₅) P2-61 CH₂CH═CH(C₄H₇) P2-62CH₂CH═CH(1-Cl—C₃H₄) P2-63 CH₂CH═CH(1-F—C₃H₄) P2-64 C≡CH P2-65 CH₂C≡CHP2-66 CH₂C≡CCH₃ P2-67 CH₂C≡CCH₂CH₃ P2-68 CH₂C≡CCl P2-69 CH₂C≡CF P2-70CH₂C≡C—I P2-71 CH₂C≡CCH₂OH P2-72 C≡COCH₃ P2-73 CH₂C≡COCH₃ P2-74CH₂C≡CCCH₂OCH₃ P2-75 C≡COCF₃ P2-76 CH₂C≡COCF₃ P2-77 C≡COCCl₃ P2-78CH₂C≡COCCl₃ P2-79 CH₂-(cyclopropyl) P2-80 CH₂-(cyclobutyl) P2-81CH₂-(1-Cl-cyclopropyl) P2-82 CH₂-(1-F-cyclopropyl) P2-83 CH₂C₆H₅ P2-84CH₂-(4-Cl)—C₆H₄ P2-85 CH₂-(4-F)—C₆H₄ P2-86 CH₂-(4-CH₃)—C₆H₄ P2-87CH₂-(4-OCH₃)—C₆H₄

Particularly preferred embodiments of combination of R¹ and R² accordingto the invention are given in Table A below, wherein each line of linesA-1 to A-56 corresponds to one particular embodiment of the invention,wherein A-1 to A-56 are also in any combination a preferred embodimentfor combinations of R¹ and R² of the present invention.

TABLE A line R¹ R² A-1 H CH₃ A-2 CH₃ CH₃ A-3 CH₂CH₃ CH₃ A-4 CH(CH₃)₂ CH₃A-5 C₃H₅ CH₃ (cyclopropyl) A-6 C₄H₇ (cyclobutyl) CH₃ A-7 C≡CCH₃ CH₃ A-8C(CH₃)₃ CH₃ A-9 CF₃ CH₃ A-10 CHF₂ CH₃ A-11 CH═CHCH₃ CH₃ A-12 C(CH₃)═CH₂CH₃ A-13 1-(Cl)-cyclopropyl CH₃ A-14 1-(F)-cyclopropyl CH₃ A-15 H CH₂CH₃A-16 CH₃ CH₂CH₃ A-17 CH₂CH₃ CH₂CH₃ A-18 CH(CH₃)₂ CH₂CH₃ A-19 C₃H₅ CH₂CH₃(cyclopropyl) A-20 C₄H₇ (cyclobutyl) CH₂CH₃ A-21 C≡CCH₃ CH₂CH₃ A-22C(CH₃)₃ CH₂CH₃ A-23 CF₃ CH₂CH₃ A-24 CHF₂ CH₂CH₃ A-25 CH═CHCH₃ CH₂CH₃A-26 C(CH₃)═CH₂ CH₂CH₃ A-27 1-(Cl)-cyclopropyl CH₂CH₃ A-281-(F)-cyclopropyl CH₂CH₃ A-29 H CH₂—CH═CH₂ A-30 CH₃ CH₂—CH═CH₂ A-31CH₂CH₃ CH₂—CH═CH₂ A-32 CH(CH₃)₂ CH₂—CH═CH₂ A-33 C₃H₅ CH₂—CH═CH₂(cyclopropyl) A-34 C₄H₇ (cyclobutyl) CH₂—CH═CH₂ A-35 C≡CCH₃ CH₂—CH═CH₂A-36 C(CH₃)₃ CH₂—CH═CH₂ A-37 CF₃ CH₂—CH═CH₂ A-38 CHF₂ CH₂—CH═CH₂ A-39CH═CHCH₃ CH₂—CH═CH₂ A-40 C(CH₃)═CH₂ CH₂—CH═CH₂ A-41 1-(Cl)-cyclopropylCH₂—CH═CH₂ A-42 1-(F)-cyclopropyl CH₂—CH═CH₂ A-43 H CH₂—C≡C—H A-44 CH₃CH₂—C≡C—H A-45 CH₂CH₃ CH₂—C≡C—H A-46 CH(CH₃)₂ CH₂—C≡C—H A-47 C₃H₅CH₂—C≡C—H (cyclopropyl) A-48 C₄H₇ (cyclobutyl) CH₂—C≡C—H A-49 C≡CCH₃CH₂—C≡C—H A-50 C(CH₃)₃ CH₂—C≡C—H A-51 CF₃ CH₂—C≡C—H A-52 CHF₂ CH₂—C≡C—HA-53 CH═CHCH₃ CH₂—C≡C—H A-54 C(CH₃)═CH₂ CH₂—C≡C—H A-551-(Cl)-cyclopropyl CH₂—C≡C—H A-56 1-(F)-cyclopropyl CH₂—C≡C—H

According to the invention, there can be zero, one, two, three or fourR³ present, namely for n is 0, 1, 2, 3 or 4.

According to one embodiment, n is 0.

According to a further embodiment, n is 1. According to still a furtherembodiment, n is 1 or 2.

According to still a further embodiment, n is 2 or 3. According to onespecific embodiment thereof, n is 2, according to a further specificembodiment, n is 3.

According to one embodiment of the invention, one R³ is attached to the2-position (R³¹).

According to one specific embodiment thereof, n is 1, according to afurther specific embodiment, n is 2.

According to one embodiment of the invention, one R³ is attached to the3-position (R³²).

According to one specific embodiment thereof, n is 1, according to afurther specific embodiment, n is 2.

According to a further embodiment of the invention, one R³ is attachedto the 5-position (R³⁴).

According to one specific embodiment thereof, n is 1, according to afurther specific embodiment, n is 2.

According to still a further embodiment, n is 1, 2 or 3 and one R³ is in2- or 6-position.

According to a further embodiment of the invention, two R³ are attachedin 2,3-position.

According to one specific embodiment thereof, n is 2, according to afurther specific embodiment, n is 3.

According to a further embodiment of the invention, two R³ are attachedin 2,5-position.

According to one specific embodiment thereof, n is 2, according to afurther specific embodiment, n is 3.

According to a further embodiment of the invention, two R³ are attachedin 2,6-position.

According to one specific embodiment thereof, n is 2, according to afurther specific embodiment, n is 3.

According to a further embodiment of the invention, two R³ are attachedin 3,5-position.

According to one specific embodiment thereof, n is 2, according to afurther specific embodiment, n is 3.

For every R³ (or R³¹, R³², R³⁴, R³⁵, respectively) that is present inthe inventive compounds, the following embodiments and preferences applyindependently of the meaning of any other R³ (or R³¹, R³², R³³, R³⁴,R³⁵, respectively) that may be present in the phenyl ring. Furthermore,the particular embodiments and preferences given herein for R³ (or R³¹,R³², R³³, R³⁴, R³⁵, respectively) apply independently for each of n=1,n=2, n=3 and n=4.

According to the invention, each R³ is independently selected fromhalogen, CN, NO₂, OH, SH, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl,C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyloxy, NH₂,NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, NH(C₃-C₆-cycloalkyl),N(C₃-C₆-cycloalkyl)₂, S(O)_(p)(C₁-C₄-alkyl), C(═O)(C₁-C₄-alkyl),C(═O)(OH), C(═O)(O—C₁-C₄-alkyl), C(═O)(NH(C₁-C₄-alkyl)),C(═O)(N(C₁-C₄-alkyl)₂), C(═O)(NH(C₃-C₆-cycloalkyl)) andC(═O)—(N(C₃-C₆-cycloalkyl)₂); wherein each of R³ is unsubstituted orfurther substituted by one, two, three or four R^(3a); wherein R^(3a) isindependently selected from halogen, CN, NO₂, OH, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₁-C₄-alkoxyand C₁-C₄-haloalkoxy.

According to one embodiment, R³ is independently selected from halogen,CN, NO₂, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,C₂-C₄-alkenyl, C₂-C₄-haloalkenyl, C₂-C₄-alkynyl, C₂-C₄-haloalkynyl,C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl, S(C₁-C₂-alkyl),S(O)(C₁-C₂-alkyl), S(O)₂(C₁-C₂-alkyl), C(═O)(C₁-C₂-alkyl), C(═O)(OH) andC(═O)(O—C₁-C₂-alkyl).

According to a further embodiment, R³ is independently selected fromhalogen, CN, NO₂, OH, SH, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl,C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyloxy, NH₂,NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, NH(C₃-C₆-cycloalkyl),N(C₃-C₆-cycloalkyl)₂, S(O)_(p)(C₁-C₄-alkyl) (p=0, 1 or 2),C(═O)(C₁-C₄-alkyl), C(═O)(OH), C(═O)(O—C₁-C₄-alkyl),C(═O)(NH(C₁-C₄-alkyl)), C(═O)(N(C₁-C₄-alkyl)₂),C(═O)(NH(C₃-C₆-cycloalkyl)) and C(═O)—(N(C₃-C₆-cycloalkyl)₂); whereineach of R³ is unsubstituted or further substituted by one, two, three orfour R^(3a), wherein R^(3a) is as defined and preferably defined herein.

According to still a further embodiment, R³ is independently selectedfrom halogen, CN, NO₂, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy, C₂-C₄-alkenyl, C₂-C₄-haloalkenyl, C₂-C₄-alkynyl,C₂-C₄-haloalkynyl, C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl,S(C₁-C₂-alkyl), S(O)(C₁-C₂-alkyl), S(O)₂(C₁-C₂-alkyl),C(═O)(C₁-C₂-alkyl), C(═O)(OH) and C(═O)(O—C₁-C₂-alkyl).

According to still a further embodiment, R³ is independently selectedfrom F, Cl, Br, CN, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy, S(C₁-C₄-alkyl), S(O)(C₁-C₄-alkyl) andS(O)₂(C₁-C₄-alkyl).

According to one specific embodiment, R³ is halogen, in particular Br, For Cl, more specifically F or Cl.

According to a further specific embodiment, R³ is CN.

According to a further specific embodiment, R³ is C₁-C₆-alkyl, inparticular C₁-C₄-alkyl, such as CH₃.

According to a further specific embodiment, R³ is C₁-C₆-haloalkyl, inparticular C₁-C₄-haloalkyl, such as CF₃, CHF₂, CH₂F, CCl₃, CHCl₂ orCH₂Cl.

According to a further specific embodiment, R³ is C₁-C₆-alkoxy, inparticular C₁-C₄-alkoxy, more specifically C₁-C₂-alkoxy such as OCH₃ orOCH₂CH₃.

According to a further specific embodiment, R³ is C₁-C₆-haloalkoxy, inparticular C₁-C₄-haloalkoxy, more specifically C₁-C₂-haloalkoxy such asOCF₃, OCHF₂, OCH₂F, OCCl₃, OCHCl₂ or OCH₂Cl, in particular OCF₃, OCHF₂,OCCl₃ or OCHCl₂.

According to still a further embodiment, R³ is C₂-C₆-alkenyl orC₂-C₆-haloalkenyl, in particular C₂-C₄-alkenyl or C₂-C₄-haloalkenyl,such as CH═CH₂.

According to still a further embodiment, R³ is C₂-C₆-alkynyl orC₂-C₆-haloalkynyl, in particular C₂-C₄-alkynyl or C₂-C₄-haloalkynyl,such as C≡CH.

According to still a further embodiment, R³ is selected fromC(═O)(C₁-C₄-alkyl), C(═O)(OH), C(═O)(O—C₁-C₄-alkyl),C(═O)(NH(C₁-C₄-alkyl)), C(═O)(N(C₁-C₄-alkyl)₂),C(═O)(NH(C₃-C₆-cycloalkyl)) and C(═O)(N(C₃-C₆-cycloalkyl)₂), inparticular selected from C(═O)(C₁-C₂-alkyl), C(═O)(OH),C(═O)(O—C₁-C₂-alkyl), C(═O)(NH(C₁-C₂-alkyl)), C(═O)(N(C₁-C₂-alkyl)₂),C(═O)(NH(C₃-C₆-cycloalkyl)) and C(═O)(N(C₃-C₆-cycloalkyl)₂). Accordingto one specific embodiment thereof, R³ is C(═O)(OH) orC(═O)(O—C₁-C₄-alkyl), in particular C(═O)(OCH₃).

According to still a further embodiment, R³ is selected fromS(C₁-C₂-alkyl), S(O)(C₁-C₂-alkyl) and S(O)₂(C₁-C₂-alkyl), in particularSCH₃, S(O)(CH₃) and S(O)₂(CH₃).

R^(3a) is independently selected from halogen, CN, NO₂, OH, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₁-C₄-alkoxyand C₁-C₄-halogenalkoxy, in particular selected from halogen, CN,C₁-C₂-alkyl, C₁-C₂-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl,C₁-C₂-alkoxy and C₁-C₂-halogenalkoxy. Specifically, R^(3a) isindependently selected from F, Cl, CN, OH, CH₃, halomethyl, cyclopropyl,halocyclopropyl, OCH₃ and halogenmethoxy.

Particularly preferred embodiments of R³ according to the invention arein Table P3 below, wherein each line of lines P3-1 to P3-16 correspondsto one particular embodiment of the invention, wherein P3-1 to P3-16 arealso in any combination with one another a preferred embodiment of thepresent invention. Thereby, for every R³ that is present in theinventive compounds, these specific embodiments and preferences applyindependently of the meaning of any other R³ that may be present in thephenyl ring:

TABLE P3 No. R³ P3-1 Cl P3-2 F P3-3 CN P3-4 NO₂ P3-5 CH₃ P3-6 CH₂CH₃P3-7 CF₃ P3-8 CHF₂ P3-9 OCH₃ P3-10 OCH₂CH₃ P3-11 OCF₃ P3-12 OCHF₂ P3-13SCH₃ P3-14 SOCH₃ P3-15 SO₂CH₃ P3-16 CO₂CH₃

Particularly preferred embodiments of (R³)_(n), according to theinvention are in Table P33 below, wherein each line of lines P33-1 toP33-60 corresponds to one particular embodiment of the invention,wherein P33-1 to P33-60 are also in any combination a preferredembodiment of the present invention.

TABLE P33 No. (R³)_(n) P33-1 —* P33-2 2-Cl P33-3 3-Cl P33-4 2-F P33-53-F P33-6 2-CN P33-7 3-CN P33-8 2-NO₂ P33-9 3-NO₂ P33-10 2-SCH₃ P33-113-SCH₃ P33-12 2-SOCH₃ P33-13 3-SOCH₃ P33-14 2-SO₂CH₃ P33-15 3-SO₂CH₃P33-16 2-CO₂CH₃ P33-17 3-CO₂CH₃ P33-18 2,3-Cl₂ P33-19 2,5-Cl₂ P33-203,5-Cl₂ P33-21 2,6-Cl₂ P33-22 2,3-F₂ P33-23 2,5-F₂ P33-24 3,5-F₂ P33-252,6-F₂ P33-26 2-F-3-Cl P33-27 2-F-6-Cl P33-28 2-Cl-3-F P33-29 2-CH₃P33-30 3-CH₃ P33-31 2-CH₂CH₃ P33-32 3-CH₂CH₃ P33-33 2-CF₃ P33-34 3-CF₃P33-35 2-CHF₂ P33-36 3-CHF₂ P33-37 2-OCH₃ P33-38 3-OCH₃ P33-39 2-OCH₂CH₃P33-40 3-OCH₂CH₃ P33-41 2-OCF₃ P33-42 3-OCF₃ P33-43 2-OCHF₂ P33-443-OCHF₂ P33-45 2,3-(CH₃)₂ P33-46 2,6-(CH₃)₂ P33-47 2,3-(CH₂CH₃)₂ P33-482,6-(CH₂CH₃)₂ P33-49 2,3-(CF₃)₂ P33-50 2,6-(CF₃)₂ P33-51 2,3-(CHF₂)₂P33-52 2,6-(CHF₂)₂ P33-53 2,3-(OCH₃)₂ P33-54 2,6-(OCH₃)₂ P33-552,3-(OCH₂CH₃)₂ P33-56 2,6-(OCH₂CH₃)₂ P33-57 2,3-(OCF₃)₂ P33-582,6-(OCF₃)₂ P33-59 2,3-(OCHF₂)₂ P33-60 2,6-(OCHF₂)₂

Each R⁴ according to the present invention is independently selectedfrom halogen, CN, NO₂, OH, SH, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl,C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyloxy, NH₂,NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, NH(C₃-C₆-cycloalkyl),N(C₃-C₆-cycloalkyl)₂, S(O)_(p)(C₁-C₄-alkyl), C(═O)(C₁-C₄-alkyl),C(═O)(OH), C(═O)(O—C₁-C₄-alkyl), C(═O)(NH(C₁-C₄-alkyl)),C(═O)(N(C₁-C₄-alkyl)₂), C(═O)(NH(C₃-C₆-cycloalkyl)) andC(═O)—(N(C₃-C₆-cycloalkyl)₂); wherein each of R⁴ is unsubstituted orfurther substituted by one, two, three or four R^(4a) independentlyselected from halogen, CN, NO₂, OH, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl, C₁-C₄-alkoxy andC₁-C₄-haloalkoxy.

According to the invention, there can be zero, one, two, three, four orfive R⁴ present, namely for m is 0, 1, 2, 3, 4 or 5. In particular, m is0, 1, 2, 3 or 4.

According to one embodiment, m is 0.

According to a further embodiment, m is 1, 2, 3 or 4, in particular 1, 2or 3, more specifically 1 or 2. According to one specific embodimentthereof, m is 1, according to a further specific embodiment, m is 2.

According to still a further embodiment, m is 2, 3 or 4.

According to still a further embodiment, m is 3.

According to one embodiment of the invention, one R⁴ is attached to thepara-position (4-position).

According to a further embodiment of the invention, one R⁴ is attachedto the meta-position (3-position).

According to a further embodiment of the invention, one R⁴ is attachedto the ortho-position (2-position).

According to a further embodiment of the invention, two R⁴ are attachedin 2,4-position.

According to a further embodiment of the invention, two R⁴ are attachedin 2,3-position.

According to a further embodiment of the invention, two R⁴ are attachedin 2,5-position.

According to a further embodiment of the invention, two R⁴ are attachedin 2,6-position.

According to a further embodiment of the invention, two R⁴ are attachedin 3,4-position.

According to a further embodiment of the invention, two R⁴ are attachedin 3,5-position.

According to a further embodiment of the invention, three R⁴ areattached in 2,4,6-position.

For every R⁴ that is present in the inventive compounds, the followingembodiments and preferences apply independently of the meaning of anyother R⁴ that may be present in the phenyl ring. Furthermore, theparticular embodiments and preferences given herein for R⁴ applyindependently for each of m=1, m=2, m=3, m=4 and m=5.

According to one embodiment, R⁴ is independently selected from halogen,CN, NO₂, OH, SH, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl,C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyloxy, NH₂,NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, NH(C₃-C₆-cycloalkyl),N(C₃-C₆-cycloalkyl)₂, S(O)_(p)(C₁-C₄-alkyl) (p=0, 1 or 2),C(═O)(C₁-C₄-alkyl), C(═O)(OH), C(═O)(O—C₁-C₄-alkyl),C(═O)(NH(C₁-C₄-alkyl)), C(═O)(N(C₁-C₄-alkyl)₂),C(═O)(NH(C₃-C₆-cycloalkyl)) and C(═O)—(N(C₃-C₆-cycloalkyl)₂); whereineach of R⁴ is unsubstituted or further substituted by one, two, three orfour independently selected R^(4a), wherein R^(4a) is as defined andpreferably defined herein.

According to a further embodiment, R⁴ is independently selected fromhalogen, CN, NO₂, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₂-C₄-alkenyl,C₂-C₄-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, NH₂,NH(C₁-C₄₂-alkyl), N(C₁-C₂-alkyl)₂, S(O)_(p)(C₁-C₂-alkyl) (p=0, 1 or 2),C(═O)(C₁-C₂-alkyl), C(═O)(OH) and C(═O)(O—C₁-C₂-alkyl), wherein each ofR⁴ is unsubstituted or further substituted by one, two, three or fourindependently selected R^(4a), wherein R^(4a) is as defined andpreferably defined herein.

According to a further embodiment, R⁴ is independently selected fromhalogen, CN, NO₂, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy, C₂-C₄-alkenyl, C₂-C₄-haloalkenyl, C₂-C₄-alkynyl,C₂-C₄-haloalkynyl, C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl,S(C₁-C₂-alkyl), S(O)(C₁-C₂-alkyl), S(O)₂(C₁-C₂-alkyl),C(═O)(C₁-C₂-alkyl), C(═O)(OH) and C(═O)(O—C₁-C₂-alkyl).

According to a further embodiment, R⁴ is independently selected fromhalogen, CN, NO₂, C₁-C₂-alkyl, C₁-C₂-haloalkyl, C₁-C₂-alkoxy,C₁-C₂-haloalkoxy, S(C₁-C₂-alkyl), S(O)(C₁-C₂-alkyl), S(O)₂(C₁-C₂-alkyl),C(═O)(OH) and C(═O)(O—C₁-C₂-alkyl).

According to a further embodiment, R⁴ is independently selected from F,Cl, Br, CN, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy, S(C₁-C₄-alkyl), S(O)(C₁-C₄-alkyl) andS(O)₂(C₁-C₄-alkyl).

According to still a further specific embodiment, R⁴ is independentlyselected from halogen, in particular from Br, F and Cl, morespecifically from F and Cl.

According to a further specific embodiment, R⁴ is CN.

According to one further embodiment R⁴ is NO₂.

According to one further embodiment R⁴ is OH.

According to one further embodiment R⁴ is SH.

According to a further specific embodiment, R⁴ is C₁-C₆-alkyl, inparticular C₁-C₄-alkyl, such as CH₃. Further appropriate alkyls areethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl.

According to a further specific embodiment, R⁴ is C₁-C₆-haloalkyl, inparticular C₁-C₄-haloalkyl, such as CF₃, CHF₂, CH₂F, CCl₃, CHCl₂ orCH₂Cl.

According to a further specific embodiment R⁴ is C₁-C₆-alkyl, preferablyC₁-C₄-alkyl, substituted by OH, more preferably CH₂OH, CH₂CH₂OH,CH₂CH₂CH₂OH, CH(CH₃)CH₂OH, CH₂CH(CH₃)OH, CH₂CH₂CH₂CH₂OH. In a specialembodiment R⁴ is CH₂OH. According to a further specific embodiment R⁴ isC₁-C₆-alkyl, preferably C₁-C₄-alkyl substituted by CN, more preferablyCH₂CN, CH₂CH₂CN, CH₂CH₂CH₂CN, CH(CH₃)CH₂CN, CH₂CH(CH₃)CN,CH₂CH—₂CH₂CH₂CN. In a special embodiment R⁴ is CH₂CH₂CN. In a furtherspecial embodiment R⁴ is CH(CH₃)CN. According to a further specificembodiment R⁴ is C₁-C₄-alkoxy-C₁-C₆-alkyl, more preferablyC₁-C₄-alkoxy-C₁-C₄-alkyl. In a special embodiment R⁴ is CH₂OCH₃. In afurther special embodiment R⁴ is CH₂CH₂OCH₃. In a further specialembodiment R⁴ is CH(CH₃)OCH₃. In a further special embodiment R⁴ isCH(CH₃)OCH₂CH₃. In a further special embodiment R⁴ is CH₂CH₂OCH₂CH₃.According to a further specific embodiment R⁴ isC₁-C₄-haloalkoxy-C₁-C₆-alkyl, more preferably C₁-C₄-alkoxy-C₁-C₄-alkyl.In a special embodiment R⁴ is CH₂OCF₃. In a further special embodimentR⁴ is CH₂CH₂OCF₃. In a further special embodiment R⁴ is CH₂OCCl₃. In afurther special embodiment R⁴ is CH₂CH₂OCCl₃.

According to a further specific embodiment, R⁴ is C₁-C₆-alkoxy, inparticular C₁-C₄-alkoxy, more specifically C₁-C₂-alkoxy such as OCH₃ orOCH₂CH₃.

According to a further specific embodiment, R⁴ is C₁-C₆-haloalkoxy, inparticular C₁-C₄-haloalkoxy, more specifically C₁-C₂-haloalkoxy such asOCF₃, OCHF₂, OCH₂F, OCCl₃, OCHCl₂ or OCH₂Cl, in particular OCF₃, OCHF₂,OCCl₃ or OCHCl₂.

According to still a further embodiment, R⁴ is C₂-C₆-alkenyl orC₂-C₆-haloalkenyl, in particular C₂-C₄-alkenyl or C₂-C₄-haloalkenyl,such as CH═CH₂, CH₂CH═CH₂, CH═CHCH₃ or C(CH₃)═CH₂.

According to a further specific embodiment R⁴ is C₂-C₆-alkenyl,preferably C₂-C₄-alkenyl, substituted by OH, more preferably, CH═CHOH,CH═CHCH₂OH, C(CH₃)═CHOH, CH═C(CH₃)OH. In a special embodiment R⁴ isCH═CHOH. In a further special embodiment R⁴ is CH═CHCH₂OH.

According to a further specific embodiment R⁴ isC₁-C₄-alkoxy-C₂-C₆-alkenyl, more preferably C₁-C₄-alkoxy-C₂-C₄-alkenyl.In a special embodiment R⁴ is CH═CHOCH₃. In a further special embodimentR⁴ is CH═CHCH₂OCH₃. According to a further specific embodiment R⁴ isC₁-C₄-haloalkoxy-C₂-C₆-alkenyl, more preferablyC₁-C₄-haloalkoxy-C₂-C₄-alkenyl. In a special embodiment R⁴ is CH═CHOCF₃.In a further special embodiment R⁴ is CH═CHCH₂OCF₃. In a further specialembodiment R⁴ is CH═CHOCCl₃. In a further special embodiment R⁴ isCH═CHCH₂OCCl₃. According to a further specific embodiment R⁴ isC₃-C₈-cycloalkyl-C₂-C₆-alkenyl, preferablyC₃-C₆-cycloalkyl-C₂-C₄-alkenyl. According to a further specificembodiment R⁴ is C₃-C₆-halocycloalkyl-C₂-C₄-alkenyl, preferablyC₃-C₈-halocycloalkyl-C₂-C₆-alkenyl.

According to still a further embodiment, R⁴ is C₂-C₆-alkynyl orC₂-C₆-haloalkynyl, in particular C₂-C₄-alkynyl or C₂-C₄-haloalkynyl,such as C≡CH, CH₂CCH or CH₂CCCH₃.

According to a further specific embodiment R⁴ is C₂-C₆-alkynyl,preferably C₂-C₄-alkynyl, substituted by OH, more preferably, CCOH,CH₂CCOH. In a special embodiment R⁴ is CCOH. In a further specialembodiment R⁴ is CH₂CCOH. According to a further specific embodiment R⁴is C₁-C₄-alkoxy-C₂-C₆-alkynyl, more preferablyC₁-C₄-alkoxy-C₂-C₄-alkynyl. In a special embodiment R⁴ is CCOCH₃. In afurther special embodiment R⁴ is CH₂CCOCH₃. According to a furtherspecific embodiment R⁴ is C₁-C₄-haloalkoxy-C₂-C₆-alkynyl, morepreferably C₁-C₄-haloalkoxy-C₂-C₄-alkynyl. In a special embodiment R⁴ isCCOCF₃. In a further special embodiment R⁴ is CH₂CCOCF₃. In a furtherspecial embodiment R⁴ is CCOCCl₃. In a further special embodiment R⁴ isCH₂CCOCCl₃. According to a further specific embodiment R⁴ isC₃-C₈-cycloalkyl-C₂-C₆-alkynyl, preferablyC₃-C₆-cycloalkyl-C₂-C₄-alkynyl. According to a further specificembodiment R⁴ is C₃-C₆-halocycloalkyl-C₂-C₄-alkynyl, preferablyC₃-C₈-halocycloalkyl-C₂-C₆-alkynyl.

According to one another embodiment R⁴ is C₃-C₈-cycloalkyl, preferablycyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in particularcyclopropyl or cyclobutyl. In a special embodiment R⁴ is cyclopropyl. Ina further special embodiment R⁴ is cyclobutyl. In a further specialembodiment R⁴ is cyclopentyl. In a further special embodiment R⁴ iscyclohexyl.

According to one another embodiment R⁴ is C₃-C₈-cycloalkoxy, preferablyC₃-C₆-cycloalkoxy. In a special embodiment R⁴ is O-cyclopropyl.

According to a specific embodiment R⁴ is C₃-C₈-halocycloalkyl, morepreferably fully or partially halogenated C₃-C₆-cycloalkyl. In a specialembodiment R⁴ is fully or partially halogenated cyclopropyl. In afurther special embodiment R⁴ is 1-Cl-cyclopropyl. In a further specialembodiment R⁴ is 2-Cl-cyclopropyl. In a further special embodiment R⁴ is1-F-cyclopropyl. In a further special embodiment R⁴ is 2-F-cyclopropyl.In a further special embodiment R⁴ is fully or partially halogenatedcyclobutyl. In a further special embodiment R⁴ is 1-Cl-cyclobutyl. In afurther special embodiment R⁴ is 1-F-cyclobutyl. In a further specialembodiment R⁴ is 3,3-Cl₂-cyclobutyl. In a further special embodiment R⁴is 3,3-F₂-cyclobutyl. According to a specific embodiment R⁴ isC₃-C₈-cycloalkyl substituted by C₁-C₄-alkyl, more preferably isC₃-C₆-cycloalkyl substituted by C₁-C₄-alkyl. In a special embodiment R⁴is 1-CH₃-cyclopropyl. According to a specific embodiment R⁴ isC₃-C₈-cycloalkyl substituted by CN, more preferably is C₃-C₆-cycloalkylsubstituted by CN. In a special embodiment R⁴ is 1-CN-cyclopropyl.According to a further specific embodiment R⁴ isC₃-C₈-cycloalkyl-C₃-C₈-cycloalkyl, preferablyC₃-C₆-cycloalkyl-C₃-C₆-cycloalkyl. In a special embodiment R⁴ iscyclopropyl-cyclopropyl. In a special embodiment R⁴ is2-cyclopropyl-cyclopropyl. According to a further specific embodiment R⁴is C₃-C₈-cycloalkyl-C₃-C₈-halocycloalkyl, preferablyC₃-C₆-cycloalkyl-C₃-C₆-halocycloalkyl.

According to one another embodiment R⁴ is C₃-C₈-cycloalkyl-C₁-C₄-alkyl,preferably C₃-C₆-cycloalkyl-C₁-C₄-alkyl. In a special embodiment R⁴ isCH(CH₃)(cyclopropyl). In a further special embodiment R⁴ isCH₂-(cyclopropyl).

According to a further preferred embodiment R⁴ isC₃-C₈-cycloalkyl-C₁-C₄-alkyl wherein the alkyl moiety can be substitutedby one, two, three or up to the maximum possible number of identical ordifferent groups R^(a) as defined and preferably herein and thecycloalkyl moiety can be substituted by one, two, three or up to themaximum possible number of identical or different groups Rb as definedand preferably herein.

According to a specific embodiment R⁴ isC₃-C₈-cycloalkyl-C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl-C₁-C₄-haloalkyl.According to a specific embodiment R⁴ isC₃-C₈-halocycloalkyl-C₁-C₄-alkyl, C₃-C₆-halocycloalkyl-C₁-C₄-alkyl. In aspecial embodiment R⁴ is fully or partially halogenatedcyclopropyl-C₁-C₄-alkyl. In a further special embodiment R⁴ is1-Cl-cyclopropyl-C₁-C₄-alkyl. In a further special embodiment R⁴ is1-F-cyclopropyl-C₁-C₄-alkyl.

According to one another embodiment R⁴ is NH₂.

According to one another embodiment R⁴ is NH(C₁-C₄-alkyl). According toa specific embodiment R⁴ is NH(CH₃). According to a specific embodimentR⁴ is NH(CH₂CH₃). According to a specific embodiment R⁴ isNH(CH₂CH₂CH₃). According to a specific embodiment R⁴ is NH(CH(CH₃)₂).According to a specific embodiment R⁴ is NH(CH₂CH₂CH₂CH₃). According toa specific embodiment R⁴ is NH(C(CH₃)₃).

According to one another embodiment R⁴ is N(C₁-C₄-alkyl)₂. According toa specific embodiment R⁴ is N(CH₃)₂. According to a specific embodimentR⁴ is N(CH₂CH₃)₂. According to a specific embodiment R⁴ isN(CH₂CH₂CH₃)₂. According to a specific embodiment R⁴ is N(CH(CH₃)₂)₂.According to a specific embodiment R⁴ is N(CH₂CH₂CH₂CH₃)₂. According toa specific embodiment R⁴ is NH(C(CH₃)₃)₂.

According to one another embodiment R⁴ is NH(C₃-C₈-cycloalkyl)preferably NH(C₃-C₆-cycloalkyl). According to a specific embodiment R⁴is NH(cyclopropyl). According to a specific embodiment R⁴ isNH(cyclobutyl). According to a specific embodiment R⁴ isNH(cyclopentyl). According to a specific embodiment R⁴ isNH(cyclohexyl).

According to one another embodiment R⁴ is N(C₃-C₈-cycloalkyl)₂preferably N(C₃-C₆-cycloalkyl)₂. According to a specific embodiment R⁴is N(cyclopropyl)₂. According to a specific embodiment R⁴ isN(cyclobutyl)₂. According to a specific embodiment R⁴ isN(cyclopentyl)₂. According to a specific embodiment R⁴ isN(cyclohexyl)₂.

According to still a further embodiment, R⁴ is selected fromC(═O)(C₁-C₄-alkyl), C(═O)(OH), C(═O)(O—C₁-C₄-alkyl),C(═O)(NH(C₁-C₄-alkyl)), C(═O)(N(C₁-C₄-alkyl)₂),C(═O)(NH(C₃-C₆-cycloalkyl)) and C(═O)(N(C₃-C₆-cycloalkyl)₂), inparticular selected from C(═O)(C₁-C₂-alkyl), C(═O)(OH),C(═O)(O—C₁-C₂-alkyl), C(═O)(NH(C₁-C₂-alkyl)), C(═O)(N(C₁-C₂-alkyl)₂),C(═O)(NH(C₃-C₆-cycloalkyl)) and C(═O)(N(C₃-C₆-cycloalkyl)₂). Accordingto one specific embodiment thereof, R⁴ is C(═O)(OH) orC(═O)(O—C₁-C₄-alkyl), in particular C(═O)(OCH₃).

According to one another embodiment R⁴ is C(═O)(—C₁-C₄-alkyl). Accordingto a specific embodiment R⁴ is C(═O)CH₃. According to a further specificembodiment R⁴ is C(═O)CH₂CH₃. According to a further specific embodimentR⁴ is C(═O)CH₂CH₂CH₃. According to a further specific embodiment R⁴ isC(═O)CH(CH₃)₂. According to a further specific embodiment R⁴ isC(═O)C(CH₃)₃.

According to one another embodiment R⁴ is C(═O)OH.

According to one another embodiment R⁴ is C(═O)(—O—C₁-C₄-alkyl).According to a specific embodiment R⁴ is C(═O)OCH₃. According to afurther specific embodiment R⁴ is C(═O)OCH₂CH₃.

According to a further specific embodiment R⁴ is C(═O)OCH₂CH₂CH₃.According to a further specific embodiment R⁴ is C(═O)OCH(CH₃)₂.According to a further specific embodiment R⁴ is C(═O)OC(CH₃)₃.

According to one another embodiment R⁴ is C(═O)—NH(C₁-C₄-alkyl).According to a specific embodiment R⁴ is C(═O)NHCH₃. According to afurther specific embodiment R⁴ is C(═O)NHCH₂CH₃.

According to a further specific embodiment R⁴ is C(═O)NHCH₂CH₂CH₃.According to a further specific embodiment R⁴ is C(═O)NHCH(CH₃)₂.According to a further specific embodiment R⁴ is C(═O)NHC(CH₃)₃.

According to one another embodiment R⁴ is C(═O)—N(C₁-C₄-alkyl)₂.According to a specific embodiment R⁴ is C(═O)N(CH₃)₂. According to afurther specific embodiment R⁴ is C(═O)N(CH₂CH₃)₂. According to afurther specific embodiment R⁴ is C(═O)N(CH₂CH₂CH₃)₂. According to afurther specific embodiment R⁴ is C(═O)N(CH(CH₃)₂)₂. According to afurther specific embodiment R⁴ is C(═O)N(C(CH₃)₃)₂.

According to one another embodiment R⁴ is C(═O)—NH(C₃-C₆-cycloalkyl).According to a specific embodiment R⁴ is C(═O)NH(cyclopropyl). Accordingto a further specific embodiment R⁴ is C(═O)NH(cyclobutyl) According toa further specific embodiment R⁴ is C(═O)NH(cyclopentyl) According to afurther specific embodiment R⁴ is C(═O)NH(cyclohexyl).

According to one another embodiment R⁴ is C(═O)—N(C₃-C₆-cycloalkyl)₂.According to a specific embodiment R⁴ is C(═O)N(cyclopropyl)₂. Accordingto a further specific embodiment R⁴ is C(═O)N(cyclobutyl)₂. According toa further specific embodiment R⁴ is C(═O)N(cyclopentyl)₂. According to afurther specific embodiment R⁴ is C(═O)N(cyclohexyl)₂.

According to still a further embodiment, R⁴ is selected fromS(C₁-C₂-alkyl), S(O)(C₁-C₂-alkyl) and S(O)₂(C₁-C₂-alkyl), in particularSCH₃, S(O)(CH₃) and S(O)₂(CH₃). According to a specific embodiment R⁴ isselected from S(C₁-C₂-haloalkyl), S(O)(C₁-C₂-haloalkyl) andS(O)₂(C₁-C₂-haloalkyl), such as SO₂CF₃.

Particularly preferred embodiments of R⁴ according to the invention arein Table P4 below, wherein each line of lines P4-1 to P4-16 correspondsto one particular embodiment of the invention, wherein P4-1 to P4-16 arealso in any combination with one another a preferred embodiment of thepresent invention. Thereby, for every R⁴ that is present in theinventive compounds, these specific embodiments and preferences applyindependently of the meaning of any other R⁴ that may be present in thephenyl ring:

TABLE P4 No. R⁴ P4-1 Cl P4-2 F P4-3 CN P4-4 NO₂ P4-5 CH₃ P4-6 CH₂CH₃P4-7 CF₃ P4-8 CHF₂ P4-9 OCH₃ P4-10 OCH₂CH₃ P4-11 OCF₃ P4-12 OCHF₂ P4-13SCH₃ P4-14 SOCH₃ P4-15 SO₂CH₃ P4-16 CO₂CH₃

Particularly preferred embodiments of (R⁴)_(m) according to theinvention are in Table P44 below, wherein each line of lines P44-1 toP44-155 corresponds to one particular embodiment of the invention,wherein P44-1 to P44-155 are also in any combination a preferredembodiment of the present invention.

TABLE P44 No. (R⁴)_(m) P44-1 —* P44-2 2-Cl P44-3 3-Cl P44-4 4-Cl P44-52-F P44-6 3-F P44-7 4-F P44-8 2-CN P44-9 3-CN P44-10 4-CN P44-11 2-NO₂P44-12 3-NO₂ P44-13 4-NO₂ P44-14 2-SCH₃ P44-15 3-SCH₃ P44-16 4-SCH₃P44-17 2-SOCH₃ P44-18 3-SOCH₃ P44-19 4-SOCH₃ P44-20 2-SO₂CH₃ P44-213-SO₂CH₃ P44-22 4-SO₂CH₃ P44-23 2-CO₂CH₃ P44-24 3-CO₂CH₃ P44-25 4-CO₂CH₃P44-26 2,3-Cl₂ P44-27 2,4-Cl₂ P44-28 2,5-Cl₂ P44-29 3,4-Cl₂ P44-303,5-Cl₂ P44-31 2,6-Cl₂ P44-32 2,3-F₂ P44-33 2,4-F₂ P44-34 2,5-F₂ P44-353,4-F₂ P44-36 3,5-F₂ P44-37 2,6-F₂ P44-38 2-F-3-Cl P44-39 2-F-4-ClP44-40 3-F-4-Cl P44-41 2-F-6-Cl P44-42 2-Cl-3-F P44-43 2-Cl-4-F P44-443-Cl-4-F P44-45 2,3,4-Cl₃ P44-46 2,4,5-Cl₃ P44-47 3,4,5-Cl₃ P44-482,4,6-Cl₃ P44-49 2,3,4-F₃ P44-50 2,4,5-F₃ P44-51 3,4,5-F₃ P44-522,4,6-F₃ P44-53 2,3-4-F₃ P44-54 2,4-F₂-3-Cl P44-55 2,6-F₂-4-Cl P44-562,5-F₂-4-Cl P44-57 2,4-Cl₂-3-F P44-58 2,6-Cl₂-4-F P44-59 2,5-Cl₂-4-FP44-60 2-CH₃ P44-61 3-CH₃ P44-62 4-CH₃ P44-63 2-CH₂CH₃ P44-64 3-CH₂CH₃P44-65 4-CH₂CH₃ P44-66 2-CF₃ P44-67 3-CF₃ P44-68 4-CF₃ P44-69 2-CHF₂P44-70 3-CHF₂ P44-71 4-CHF₂ P44-72 2-OCH₃ P44-73 3-OCH₃ P44-74 4-OCH₃P44-75 2-OCH₂CH₃ P44-76 3-OCH₂CH₃ P44-77 4-OCH₂CH₃ P44-78 2-OCF₃ P44-793-OCF₃ P44-80 4-OCF₃ P44-81 2-OCHF₂ P44-82 3-OCHF₂ P44-83 4-OCHF₂ P44-842,3-(CH₃)₂ P44-85 2,4-(CH₃)₂ P44-86 3,4-(CH₃)₂ P44-87 2,6-(CH₃)₂ P44-882,3-(CH₂CH₃)₂ P44-89 2,4-(CH₂CH₃)₂ P44-90 3,4-(CH₂CH₃)₂ P44-912,6-(CH₂CH₃)₂ P44-92 2,3-(CF₃)₂ P44-93 2,4-(CF₃)₂ P44-94 3,4-(CF₃)₂P44-95 2,6-(CF₃)₂ P44-96 2,3-(CHF₂)₂ P44-97 2,4-(CHF₂)₂ P44-983,4-(CHF₂)₂ P44-99 2,6-(CHF₂)₂ P44-100 2,3-(OCH₃)₂ P44-101 2,4-(OCH₃)₂P44-102 3,4-(OCH₃)₂ P44-103 2,6-(OCH₃)₂ P44-104 2,3- (OCH₂CH₃)₂ P44-1052,4- (OCH₂CH₃)₂ P44-106 3,4- (OCH₂CH₃)₂ P44-107 2,6- (OCH₂CH₃)₂ P44-1082,3-(OCF₃)₂ P44-109 2,4-(OCF₃)₂ P44-110 3,4-(OCF₃)₂ P44-111 2,6-(OCF₃)₂P44-112 2,3-(OCHF₂)₂ P44-113 2,4-(OCHF₂)₂ P44-114 3,4-(OCHF₂)₂ P44-1152,6-(OCHF₂)₂ P44-116 2,3,4-(CH₃)₃ P44-117 2,4,5-(CH₃)₃ P44-1183,4,5-(CH₃)₃ P44-119 2,4,6-(CH₃)₃ P44-120 2,3,4- (CH₂CH₃)₃ P44-1212,4,5- (CH₂CH₃)₃ P44-122 3,4,5- (CH₂CH₃)₃ P44-123 2,4,6- (CH₂CH₃)₃P44-124 2,3,4-(CF₃)₃ P44-125 2,4,5-(CF₃)₃ P44-126 3,4,5-(CF₃)₃ P44-1272,4,6-(CF₃)₃ P44-128 2,3,4-(CHF₂)₃ P44-129 2,4,5-(CHF₂)₃ P44-1303,4,5-(CHF₂)₃ P44-131 2,4,6-(CHF₂)₃ P44-132 2,3,4-(OCH₃)₃ P44-1332,4,5-(OCH₃)₃ P44-134 3,4,5-(OCH₃)₃ P44-135 2,4,6-(OCH₃)₃ P44-136 2,3,4-(OCH₂CH₃)₃ P44-137 2,4,5- (OCH₂CH₃)₃ P44-138 3,4,5- (OCH₂CH₃)₃ P44-1392,4,6- (OCH₂CH₃)₃ P44-140 2,3,4-(OCF₃)₃ P44-141 2,4,5-(OCF₃)₃ P44-1423,4,5-(OCF₃)₃ P44-143 2,4,6-(OCF₃)₃ P44-144 2,3,4-(OCHF₂)₃ P44-1452,4,5-(OCHF₂)₃ P44-146 3,4,5-(OCHF₂)₃ P44-147 2,4,6-(OCHF₂)₃ P44-1482-CF₃-4-Cl P44-149 2-CF₃-4-F P44-150 2-Cl-4-CF₃ P44-151 2-F-4-CF₃P44-152 2-CN-4-Cl P44-153 2-CN-4-F P44-154 2-Cl-4-CN P44-155 2-F-4-CN

In particular, in the inventive process, compounds III.a are used toobtain compounds II.a and, then may be further reacted to compounds Ia,and optionally further reacted to the respective I-1 compounds(containing “OR²” see above):

Wherein the substituents are as defined and preferably defined above. Inparticular, the substituents have the following preferred meanings.There, the specific meanings of the respective substituents are in eachcase on their own but also in any combination with one another,particular embodiments of the present invention.

According to one particular embodiment of the invention, in thecompounds I (or I-1), II and III, respectively, R¹ is (C₁-C₄)-alkyl,(C₃-C₆)-cycloalkyl or (C₂-C₄)-alkinyl. Preferably, R¹ is (C₁-C₄)-alkyl,(C₃)-cycloalkyl or (C₃)-alkinyl. In one specific embodiment thereof, R¹is CH₃. In a further specific embodiment R¹ is C₂H₅. In still a furtherspecific embodiment R¹ is n-(C₃H₇). In still a further specificembodiment R¹ is i-(C₃H₇). In still a further specific embodiment R¹ isC(CH₃)₃. In still a further embodiment R¹ is cyclopropyl. In still afurther embodiment R¹ is C≡C—CH₃.

According to one particular embodiment of the invention, in thecompounds I-1, R² is (C₁-C₃)-alkyl, (C₂-C₄)-alkenyl or (C₂-C₄)-alkynyl,in particular hydrogen, (C₁-C₃)-alkyl, (C₂-C₃)-alkenyl or(C₂-C₄)-alkynyl. Preferably, R² is (C₁-C₃)-alkyl. In a further specificembodiment R² is CH₃. In still a further specific embodiment R² is C₂H₅.In still a further specific embodiment R² is n-(C₃H₇). In still afurther specific embodiment R² is i-(C₃H₇). In still a further specificembodiment R² is CH₂CH═CH₂ (allyl). In still a further specificembodiment R² is CH₂C(CH₃)═CH₂. In still a further specific embodimentR² is CH₂C≡CH.

According to one particular embodiment of the invention, in thecompounds I (or I-1), II and III, respectively, R³ is Cl or CF₃. In oneembodiment R³ is C₁. In the further embodiment, R³ is CF₃.

According to one particular embodiment of the invention, in thecompounds I (or I-1), II and III, respectively, R⁴ is Cl or F. In oneembodiment R⁴ is Cl . In the further embodiment R⁴ is F.

Specifically, the following compounds I.1 to I.18 and I.19 to I.31 canadvantageously be prepared using the process according to the presentinvention:

-   compound I.1    2-[2-chloro-4-(4-chlorophenoxy)phenyl]-1-(1,2,4-triazol-1-yl)pent-3-yn-2-ol;-   compound I.2    1-[2-chloro-4-(4-chlorophenoxy)phenyl]-1-cyclopropyl-2-(1,2,4-triazol-1-yl)ethanol;-   compound I.3    2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-(1,2,4-triazol-1-yl)propan-2-ol;-   compound I.4    1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-cyclopropyl-2-(1,2,4-triazol-1-yl)ethanol;-   compound I.5    2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-3-methyl-1-(1,2,4-triazol-1-yl)butan-2-ol;-   compound I.6    1-[2-[2-chloro-4-(4-chlorophenoxy)phenyl]-2-methoxy-pent-3-ynyl]-1,2,4-triazole;-   compound I.7    2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-(1,2,4-triazol-1-yl)butan-2-ol;-   compound I.8    1-[2-[2-chloro-4-(4-chlorophenoxy)phenyl]-2-cyclopropyl-2-methoxy-ethyl]-1,2,4-triazole;-   compound I.9    1-[2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methoxy-propyl]-1,2,4-triazole;-   compound I.10    2-[2-chloro-4-(4-chlorophenoxy)phenyl]-3,3-dimethyl-1-(1,2,4-triazol-1-yl)butan-2-ol,-   compound I.11    1-[2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-cyclopropyl-2-methoxy-ethyl]-1,2,4-triazole;-   compound I.12    1-[2-[2-chloro-4-(4-chlorophenoxy)phenyl]-2-methoxy-3,3-dimethyl-butyl]-1,2,4-triazole;-   compound I.13    1-[2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methoxy-butyl]1,2,4-triazole;-   compound I.14    2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-(1,2,4-triazol-1-yl)pent-3-yn-2-ol;-   compound I.15    1-[2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methoxy-pent-3-ynyl]-1,2,4-triazole;-   compound I.16    2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-(1,2,4-triazol-1-yl)but-3-yn-2-ol;-   compound I.17    2-[2-chloro-4-(4-chlorophenoxy)phenyl]-1-(1,2,4-triazol-1-yl)propan-2-ol;    and-   compound I.18    2-[2-chloro-4-(4-fluorophenoxy)phenyl]-1-(1,2,4-triazol-1-yl)propan-2-ol.-   compound I.19    2-[2-chloro-4-(4-chlorophenoxy)phenyl]-3-methyl-1-(1,2,4-triazol-1-yl)butan-2-01;-   compound I.20    1-[2-[2-chloro-4-(4-chlorophenoxy)phenyl]-2-methoxy-propyl]-1,2,4-triazole;-   compound I.21    1-[2-[2-chloro-4-(4-chlorophenoxy)phenyl]-2-methoxy-butyl]-1,2,4-riazole;-   compound I.22    1-[2-[2-chloro-4-(4-chlorophenoxy)phenyl]-2-methoxy-pentyl]-1,2,4-triazole;-   compound I.23    2-[2-chloro-4-(4-chlorophenoxy)phenyl]-1,1,1-trifluoro-3-(1,2,4-triazol-1-yl)propan-2-ol;-   compound I.24    2-[2-chloro-4-(4-chlorophenoxy)phenyl]-3-fluoro-1-(1,2,4-triazol-1-yl)butan-2-ol    hydrochloride;-   compound I.25    2-[2-chloro-4-(4-chlorophenoxy)phenyl]-1-(1,2,4-triazol-1-yl)pent-4-yn-2-ol;-   compound I.26    2-[2-chloro-4-(4-chlorophenoxy)phenyl]-1-methoxy-3-(1,2,4-triazol-1-yl)propan-2-ol;-   compound I.27    2-[2-chloro-4-(4-fluorophenoxy)phenyl]-1-methoxy-3-(1,2,4-triazol-1-yl)propan-2-ol;-   compound I.28    2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-(1,2,4-triazol-1-yl)pentan-2-ol;-   compound I.29 and    2-[4-(4-fluorophenoxy)-2-(trifluoromethyl)phenyl]-1-(1,2,4-triazol-1-yl)propan-2-ol;-   compound I.30    2-[2-chloro-4-(4-chlorophenoxy)phenyl]-1-(1,2,4-triazol-1-yl)butan-2-ol;    and-   compound I.31    2-[2-chloro-4-(4-chlorophenoxy)phenyl]-1-(1,2,4-triazol-1-yl)pentan-2-ol.

Specifically, the following compounds IC.1 to IC.7 can advantageously beprepared using the process according to the present invention:

-   compound IC.1    2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-(1,2,4-triazol-1-yl)propan-2-ol;-   compound IC.2    1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-cyclopropyl-2-(1,2,4-triazol-1-yl)ethanol;-   compound IC.3    2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-3-methyl-1-(1,2,4-triazol-1-yl)butan-2-ol;-   compound IC.4    2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-(1,2,4-triazol-1-yl)butan-2-ol;-   compound IC.5    1-[2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methoxy-propyl]-1,2,4-triazole;-   compound IC.6    1-[2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-cyclopropyl-2-methoxy-ethyl]-1,2,4-triazole;-   compound IC.7    1-[2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methoxy-butyl]1,2,4-triazole.

Compounds I comprise chiral centers and they are generally obtained inthe form of racemates. The R- and S-enantiomers of the compounds can beseparated and isolated in pure form with methods known by the skilledperson, e.g. by using chiral HPLC. Furthermore, components I can bepresent in different crystal modifications, which may differ inbiological activity.

The compounds according to the invention may be present in variouscrystal modifications.

They are likewise provided by the present invention.

Furthermore, using the inventive crystallization step, solvates mayoccur, in particular from any one of compounds I.1 to I.18 that arelikewise comprised by the present invention. A further aspect of theinvention is, therefore, a crystalline solvate of compound I, inparticular a crystalline solvate with a compounds I selected from I.1,I.2, I.3, I.4, I.5, I.6, I.7, I.8, I.9, I.10, I.11, I.12, I.13, I.14,I.15, I.16, I.17 and I.18. In particular, the solvate is formed using analiphatic alcohol as detailed abovem, in particular methanol or ethanol.

It was surprisingly found that the process of the present inventionallows to prepare a specific crystalline form of2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-(1,2,4-triazol-1-yl)propane-2-ol(compound I.3), hereinafter also termed form A of compound I.3, whichhas not yet been described so far and which has beneficial properties incomparison with the known solid forms of the compound I.3.2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-(1,2,4-triazol-1-yl)propane-2-olis a compound of formula I, where R1 is methyl, (R³)_(n) istrifloromethyl, which is located in the meta position with respect tothe phenoxy radical and is (R⁴)_(m) chlorine, which is located para withrespect to the oxygen atom.

Form A of compound I.3 can be characterized by its X-ray powderdiffractogram at 25° C. using Cu—K_(α) radiation. Said X-ray powderdiffractogram shows at least six, in particular at least 8, moreparticularly at least 10 or 12 and especially all of the fifteenfollowing reflexes, given in the following table 1 as 2θ values andd-spacings:

TABLE 1 Relevant reflections in the XRPD pattern of crystalline form ofForm A of compound I.3 2θ values [°] d [Å]  9.16 ± 0.2 9.65 13.95 ± 0.26.35 15.35 ± 0.2 5.77 16.04 ± 0.2 5.52 16.51 ± 0.2 5.37 17.17 ± 0.2 5.1718.26 ± 0.2 4.86 18.89 ± 0.2 4.70 20.59 ± 0.2 4.31 21.11 ± 0.2 4.2121.49 ± 0.2 4.14 22.33 ± 0.2 3.98 22.60 ± 0.2 3.93 23.26 ± 0.2 3.8226.46 ± 0.2 3.37

A skilled person appreciates understands that Cu—K_(α) radiation iselectromagnetic radiation having maximum intensity at wavelength of1.54178 Å.

Therefore, a further aspect of the present invention relates to acrystalline form A of2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-(1,2,4-triazol-1-yl)propane-2-ol,as described above.

The crystal form A of compound I.3 according to the invention is easierto handle than the previously known form of compound I.3 (known e.g.from PCT/EP2012/063626), since during production form A is obtained inthe form of discrete crystals or crystallites having increased particlesize in comparison to other forms of compound I.3. Increased particlesize and the compact habit of form A facilitates filtration from motherliquour and allows easier drying of the solid material.

Compared to the known forms of compound I.3, pure form A is likely todisplay increased stability with regard to conversion into anothermodification. The stability of formulations which contain the compoundI.3 in form A is likely higher than the stability of formulations whichcontain mixtures of different modifications of compound I.3. The terms“pure form A” should be understood to mean that the proportion of themodification in question, based on the total quantity of compound I.3,is at least 80% by weight in particular at least 90% by weight andespecially at least 95% by weight. Accordingly, a further object of thepresent invention relates a composition of the compound I.3 which atleast 80% by weight, in particular at least 90% by weight or at least95% by weight consists of the crystalline form A, based on the totalamount of the compound I.3, contained in the composition.

Furthermore, form A of compound I.3 may be distinguished from the knownforms of compound I.3 by differences in one or more of the followingproperties: solubility, vapor pressure, dissolution rate, stabilityagainst a phase change into a different modification, stability duringgrinding, suspension stability, optical and mechanical properties,hygroscopicity, crystal form and size, filterability, density, meltingpoint, stability to decomposition, color and even chemical reactivity orbiological activity.

Studies on single crystals of form A of compound I.3 demonstrate thatthe underlying crystal structure is orthorhombic. The unit cell has thespace group Iba2. The characteristic data of the crystal structure ofform A (determined at 100 K, Cu—K_(α) radiation) are compiled in thefollowing table 2.

TABLE 2 Crystallographic characteristics of form A of compound I.3Parameter Form A class orthorhombic space group lba2 a 38.612(2) Å b8.5677(5) Å c 10.6625(6) Å  α 90° β 90° γ 90° volume  3527.3(3) Å³ Z 8 Rfactor 10.81% a, b, c = unit cell length α, β, γ = unit cell angle Z =number of molecules in the unit cell

Form A of compound I.3 displays a thermogram with a characteristicmelting peak in the range from 120 to 135° C. The melting point,determined as the onset of the melting peak, typically lies in the rangefrom about 125° C. to 126° C. The values quoted here relate to valuesdetermined by differential calorimetry (differential scanningcalorimetry: DSC, crimped but vented aluminium pans, heating rate 10K/min, vented with nitrogen 150 ml/min).

Form A of compound I.3 was prepared by example C.1 as describedhereinafter, followed by crystallization from a solution of compound I.3in an aromatic hydrocarbon solvents, such as toluene. Preferably,crystallization is achieved by cooling a hot solution of compound I.3 inthe aromatic hydrocarbon solvent. Preferably, the hot solution has atemperature of at least 60°, e.g. from 70 to 110° C. Preferably coolingis performed with controlled cooling rate, the cooling rate being inparticular from 1 to 20 k/h, in particular from 2 to 10 k/h. Singlecrystals of form A of compound I.3 were obtained from slow evaporationof a solution of compound I.3 in acetonitrile.

The crystallization of form A can be promoted or accelerated by seedingwith seed crystals of form A of compound I.3, for example by adding seedcrystals of form 3 before or during the crystallization. If seedcrystals are added during the crystallization, the quantity thereof istypically 0.001 to 10 wt. %, often 0.005 to 5 wt. %, in particular 0.01to 1 wt. % and especially 0.05 to 0.5 wt. %, based on the total amountof compound I.3 to be crystallized.

It was also surprisingly found that the process of the present inventionallows to prepare a specific crystalline form of2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-3-methyl-1-(1,2,4-triazol-1-yl)butane-2-ol(compound I.5), hereinafter also termed form A of compound I.5, whichhas not yet been described so far and which has beneficial properties incomparison with the known solid forms of the compound I.5.2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-3-methyl-1-(1,2,4-triazol-1-yl)butane-2-olis a compound of formula I, where R¹ is isopropyl, (R³)_(n) istrifloromethyl, which is located in the meta position with respect tothe phenoxy radical and is (R⁴)_(m) chlorine, which is located para withrespect to the oxygen atom.

Form A of compound I.5 can be characterized by its X-ray powderdiffractogram at 25° C. and Cu—K_(α) radiation, which shows at leastsix, in particular at least 8, more particularly at least 10 or 12 andespecially all of the fourteen following reflexes, given as 2θ valuesand d-spacings in the following table 3:

TABLE 3 Relevant reflections in the XRPD pattern of compound I.5 form A2θ values [°] d [Å]  6.26 ± 0.2 14.11 11.68 ± 0.2 7.58 12.52 ± 0.2 7.0713.64 ± 0.2 6.49 14.69 ± 0.2 6.03 18.84 ± 0.2 4.71 19.36 ± 0.2 4.5920.44 ± 0.2 4.35 21.32 ± 0.2 4.17 22.02 ± 0.2 4.04 22.99 ± 0.2 3.8724.18 ± 0.2 3.68 25.22 ± 0.2 3.53 25.68 ± 0.2 3.47

Therefore, a further aspect of the present invention relates to acrystalline form A of2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-3-methyl-1-(1,2,4-triazol-1-yl)butane-2-ol,as described above.

The crystal form A of compound I.5 according to the invention is easierto handle than the previously known forms of compound I.5 (known e.g.from PCT/EP2012/063626), since during production form A is obtained inthe form of discrete crystals or crystallites having increased particlesize in comparison to other forms of compound I.5. Increased particlesize and the compact habit of form A facilitates filtration from motherliquour and allows easier drying of the solid material.

Compared to the known forms of compound I.5, pure form A is likely todisplay increased stability with regard to conversion into anothermodification. The stability of formulations which contain the compoundI.5 in form A is likely higher than the stability of formulations whichcontain mixtures of different modifications of compound I.3. The terms“pure form A” should be understood to mean that the proportion of themodification in question, based on the total quantity of compound I.5,is at least 80% by weight in particular at least 90% by weight andespecially at least 95% by weight. Accordingly, a further object of thepresent invention relates a composition of the compound I.3 which atleast 80% by weight, in particular at least 90% by weight or at least95% by weight consists of the crystalline form A, based on the totalamount of the compound I.5, contained in the composition.

Furthermore, form A of compound I.5 may be distinguished from the knownforms of compound I.5 by differences in one or more of the followingproperties: solubility, vapor pressure, dissolution rate, stabilityagainst a phase change into a different modification, stability duringgrinding, suspension stability, optical and mechanical properties,hygroscopicity, crystal form and size, filterability, density, meltingpoint, stability to decomposition, color and even chemical reactivity orbiological activity.

Studies on single crystals of form A demonstrate that the underlyingcrystal structure is monoclinic. The unit cell has the space groupP2₁/n. The characteristic data of the crystal structure of form A(determined at 100 K, Cu—K_(α) radiation) are compiled in the followingtable 4.

TABLE 4 Crystallographic characteristics of form A of compound 1.5Parameter Form A class Monoclinic space group P2₁/n a  8.0285(2) Å b27.8467(6) Å c  9.1925(2) Å α 90° β 103.3169(10)° γ 90° volume 1991.32(8) Å³ Z 4 R factor 2.80% a, b, c = unit cell length α, β, γ =unit cell angle Z = number of molecules in the unit cell

Form A of compound I.5 displays a thermogram with a characteristicmelting peak in the range from 109 to 116° C. The melting point,determined as the onset of the melting peak, typically lies in the rangefrom about 114° C. to 115° C. The values quoted here relate to valuesdetermined by differential calorimetry (differential scanningcalorimetry: DSC, crimped but vented aluminium pans, heating rate 10K/min, vented with nitrogen 150 ml/min).

Form A of compound I.5 was prepared by example C.3 as describedhereinafter, followed by crystallization from a solution of compound I.5in lower alkanol, such as methanol. Preferably, crystallization isachieved by cooling a hot solution of compound I.5 in the alkanol.Preferably, the hot solution has a temperature of at least 50°, e.g.from 50 to 70° C. Preferably cooling is performed with controlledcooling rate, the cooling rate being in particular from 1 to 20 k/h, inparticular from 2 to 10 k/h. Single crystals of form A of compound I.5were obtained by diffusion of heptane into a solution of compound I.5 in2-propanol.

The crystallization of form A can be promoted or accelerated by seedingwith seed crystals of form A of compound I.5, for example by adding seedcrystals of form A before or during the crystallization. If seedcrystals are added during the crystallization, the quantity thereof istypically 0.001 to 10 wt. %, often 0.005 to 5 wt. %, in particular 0.01to 1 wt. % and especially 0.05 to 0.5 wt. %, based on the total amountof compound I.5 to be crystallized.

Just like the known forms of compounds I.3 and I.5, forms A of compoundsI.3 and I.5, respectively are suitable as fungicides, i.e. forcontrolling harmful fungi, in particular for controlling plantpathogenic fungi. However they are superior to these as regards itshandling and formulation properties. Hence, the invention relates to theuse of forms A and B of compounds I.3 and I.5, respectively forcontrolling harmful fungi, in particular for controlling plantpathogenic fungi.

The invention thus also relates to agrochemical compositions containingthe crystalline form A of compound I.3 or the crystalline form A ofcompound I.5, and also one or more auxiliaries, conventionally used forthe formulation of plant protection agents, in particular plantprotection agents in the form of aqueous suspension concentrates(so-called SC's) or non-aqueous suspension concentrates (so-calledOD's), and plant protection agents in the form of powders (so-calledWP's) and granules (so-called WG's) dispersible in water.

The invention also relates to a method for controlling harmful fungi, inparticular for controlling plant pathogenic fungi, which methodcomprises treating the fungi or the plants, the soil, seeds ornon-living materials with the crystalline form A of compound I.3 or withthe crystalline form A of compound I.5, preferably as a suitable activesubstance preparation, is used on plants, their habitat and/or on seeds.

The crystalline form A of compound I.3 as well as the crystalline form Aof compound I.5 and the agrochemical compositions which contain thecrystalline form A of compound I.3 or the crystalline form A of compoundI.5 may be used for combating a broad spectrum of phytopathogenic fungi,including soil-borne fungi, which derive especially from the classes ofthe Plasmodiophoromycetes, Peronosporomycetes (syn. Oomycetes),Chytridiomycetes, Zygomycetes, Ascomycetes, Basidiomycetes andDeuteromycetes (syn. Fungi imperfecti). Some are systemically effectiveand they can be used in crop protection as foliar fungicides, fungicidesfor seed dressing and soil fungicides. Moreover, they are suitable forcontrolling harmful fungi, which inter alia occur in wood or roots ofplants.

The crystalline form A of compound I.3 as well as the crystalline form Aof compound I.5 and the agrochemical compositions which contain thecrystalline form A of compound I.3 or the crystalline form A of compoundI.5 are particularly important in the control of a multitude ofphytopathogenic fungi on various cultivated plants, such as cereals, e.g. wheat, rye, barley, triticale, oats or rice; beet, e. g. sugar beetor fodder beet; fruits, such as pomes, stone fruits or soft fruits, e.g. apples, pears, plums, peaches, almonds, cherries, strawberries,raspberries, blackberries or gooseberries; leguminous plants, such aslentils, peas, alfalfa or soybeans; oil plants, such as rape, mustard,olives, sunflowers, coconut, cocoa beans, castor oil plants, oil palms,ground nuts or soybeans; cucurbits, such as squashes, cucumber ormelons; fiber plants, such as cotton, flax, hemp or jute; citrus fruit,such as oranges, lemons, grapefruits or mandarins; vegetables, such asspinach, lettuce, asparagus, cabbages, carrots, onions, tomatoes,potatoes, cucurbits or paprika; lauraceous plants, such as avocados,cinnamon or camphor; energy and raw material plants, such as corn,soybean, rape, sugar cane or oil palm; corn; tobacco; nuts; coffee; tea;bananas; vines (table grapes and grape juice grape vines); hop; turf;sweet leaf (also called Stevia); natural rubber plants or ornamental andforestry plants, such as flowers, shrubs, broad-leaved trees orevergreens, e. g. conifers; and on the plant propagation material, suchas seeds, and the crop material of these plants.

The crystalline form A of compound I.3 as well as the crystalline form Aof compound I.5 and the agrochemical compositions which contain thecrystalline form A of compound I.3 or the crystalline form A of compoundI.5 may also be used for protecting plant propagation material againstinfection with phytopathogenic fungi. The term “plant propagationmaterial” is to be understood to denote all the generative parts of theplant such as seeds and vegetative plant material such as cuttings andtubers (e. g. potatoes), which can be used for the multiplication of theplant. This includes seeds, roots, fruits, tubers, bulbs, rhizomes,shoots, sprouts and other parts of plants, including seedlings and youngplants, which are to be transplanted after germination or afteremergence from soil. These young plants may also be protected beforetransplantation by a total or partial treatment by immersion or pouring.

The crystalline form A of compound I.3 as well as the crystalline form Aof compound I.5 and the agrochemical compositions which contain thecrystalline form A of compound I.3 or the crystalline form A of compoundI.5 may also be used for controlling harmful fungi in the protection ofstored products or harvest and in the protection of materials. The term“protection of materials” is to be understood to denote the protectionof technical and non-living materials, such as adhesives, glues, wood,paper and paperboard, textiles, leather, paint dispersions, plastics,coiling lubricants, fiber or fabrics, against the infestation anddestruction by harmful microorganisms, such as fungi and bacteria. As tothe protection of wood and other materials.

Further, crystalline form A of compound I.3 as well as the crystallineform A of compound I.5 and the agrochemical compositions which containthe crystalline form A of compound I.3 or the crystalline form A ofcompound I.5 can also be used in crops which through breeding includinggenetic engineering methods are tolerant towards insect or fungalattack. Plants that have been modified by breeding, mutagenesis orgenetic engineering, e. g. have been rendered tolerant to applicationsof specific classes of herbicides, such as auxin herbicides such asdicamba or 2,4-D; bleacher herbicides such as hydroxylphenylpyruvatedioxygenase (HPPD) inhibitors or phytoene desaturase (PDS) inhibittors;acetolactate synthase (ALS) inhibitors such as sulfonyl ureas orimidazolinones; enolpyruvylshikimate-3-phosphate synthase (EPSPS)inhibitors, such as glyphosate; glutamine synthetase (GS) inhibitorssuch as glufosinate; protoporphyrinogen-IX oxidase inhibitors; lipidbiosynthesis inhibitors such as acetyl CoA carboxylase (ACCase)inhibitors; or oxynil (i. e. bromoxynil or ioxynil) herbicides as aresult of conventional methods of breeding or genetic engineering.Furthermore, plants have been made resistant to multiple classes ofherbicides through multiple genetic modifications, such as resistance toboth glyphosate and glufosinate or to both glyphosate and a herbicidefrom another class such as ALS inhibitors, HPPD inhibitors, auxinherbicides, or ACCase inhibitors. These herbicide resistancetechnologies are e. g. described in Pest Managem. Sci. 61, 2005, 246;61, 2005, 258; 61, 2005, 277; 61, 2005, 269; 61, 2005, 286; 64, 2008,326; 64, 2008, 332; Weed Sci. 57, 2009, 108; Austral. J. Agricult. Res.58, 2007, 708; Science 316, 2007, 1185; and references quoted therein.Several cultivated plants have been rendered tolerant to herbicides byconventional methods of breeding (mutagenesis), e. g. Clearfield® summerrape (Canola, BASF SE, Germany) being tolerant to imidazolinones, e. g.imazamox, or ExpressSun® sunflowers (DuPont, USA) being tolerant tosulfonyl ureas, e. g. tribenuron. Genetic engineering methods have beenused to render cultivated plants such as soybean, cotton, corn, beetsand rape, tolerant to herbicides such as glyphosate and glufosinate,some of which are commercially available under the trade namesRoundupReady® (glyphosate-tolerant, Monsanto, U.S.A.), Cultivance®(imidazolinone tolerant, BASF SE, Germany) and LibertyLink®(glufosinate-tolerant, Bayer CropScience, Germany).

Form A of compound I.3 or with form A of compound I.5 and compositionsthereof, respectively, may be used for improving the health of a plant.The invention also relates to a method for improving plant health bytreating a plant, its propagation material and/or the locus where theplant is growing or is to grow with an effective amount of compounds Iand compositions thereof, respectively. The term “plant health” is to beunderstood to denote a condition of the plant and/or its products whichis determined by several indicators alone or in combination with eachother such as yield (e. g. increased biomass and/or increased content ofvaluable ingredients), plant vigor (e. g. improved plant growth and/orgreener leaves (“greening effect”)), quality (e. g. improved content orcomposition of certain ingredients) and tolerance to abiotic and/orbiotic stress. The above identified indicators for the health conditionof a plant may be interdependent or may result from each other.

Form A of compound I.3 or form A of compound I.5 are employed as such orin form of compositions by treating the fungi or the plants, plantpropagation materials, such as seeds, soil, surfaces, materials or roomsto be protected from fungal attack with a fungicidally effective amountof the active substances. The application can be carried out both beforeand after the infection of the plants, plant propagation materials, suchas seeds, soil, surfaces, materials or rooms by the fungi. Plantpropagation materials may be treated with form A of compound I.3 or withform A of compound I.5 as such or a composition comprising form A ofcompound I.3 or form A of compound I.5 prophylactically either at orbefore planting or transplanting.

The crystalline form A of compound I.3 as well as the crystalline form Aof compound I.5 and the agrochemical compositions which contain thecrystalline forms A of compounds I.3 or I.5, respectively, can, forexample, be used in the form of directly sprayable aqueous solutions,powders, suspensions and also high concentration aqueous, oily or othersuspensions, oil suspensions, pastes, dusting agents, scattering agentsor granules by spraying, misting, dusting, scattering or pouring. Theuse forms are determined by the use purposes; in each case, they shouldensure the finest possible distribution of the active substancesaccording to the invention.

The invention also relates to agrochemical compositions comprising anauxiliary and forms A of compounds I.3 or I.5 according to theinvention.

The agrochemical compositions according to the invention contain eitherform A of compound I.3 or form A of compound I.5. The purity, based onthe modification in question, is preferably at least 80 wt. %, inparticular at least 90% or at least 95%, based on the total amount ofcompound I.3 or I.5, respectively. However, the purity, based on themodification in question, may also be as low as 5% or at least 10%,based on the total amount of compound I.3 or I.5, respectively.

The agrochemical compositions according to the invention also containone or more auxiliaries, which are usual for the formulation of plantprotection agents. In such agrochemical compositions, the quantity ofactive substance, i.e. the total quantity of compounds I.3 or I.5 and ofother active substances, if present, normally lies in the range from 1to 98 wt. %, in particular in the range from 5 to 95 wt. %, based on thetotal weight of the agrochemical compositions, the remainder being oneor more auxiliaries.

Suitable auxiliaries are liquid carriers, solid carriers or fillers,surfactants, dispersants, emulsifiers, wetters, adjuvants, solubilizers,penetration enhancers, protective colloids, adhesion agents, thickeners,humectants, repellents, attractants, feeding stimulants,compatibilizers, bactericides, anti-freezing agents, anti-foamingagents, colorants, tackifiers and binders.

All solid and liquid substances which are normally used as carriers inplant protection agents, in particular in herbicide formulations arepossible as carriers.

Solid carriers are for example mineral earths such as silicic acids,silica gels, silicates, talc, kaolin, limestone, lime, chalk, bole,loess, clay, dolomite, diatomaceous earth, calcium and magnesiumsulfate, magnesium oxide, ground plastics, fertilizers such as ammoniumsulfate, ammonium phosphate, ammonium nitrate, ureas and plant productssuch as cereal flour, tree bark, wood and nutshell flour, cellulosepowder and other solid carriers.

Liquid carriers, as well as water, are also organic liquids, for examplemineral oil fractions of medium to high boiling point such as keroseneand diesel oil, also coal tar oils and oils of plant or animal origin,aliphatic, cyclic and aromatic hydrocarbons, for example paraffins,tetrahydronaphthalene, alkylated naphthalenes and derivatives thereof,alkylated benzenes and derivatives thereof, including aromatic andnon-aromatic hydrocarbon mixtures, for example the products marketedunder the trade names Exxsol and Solvesso, alcohols such as propanol,butanol and cyclohexanol.

Typical further auxiliaries include surface-active substances, inparticular those wetting agents, emulsifiers and dispersant (additives)normally used in plant protection agents, and also viscosity-modifyingadditives (thickeners and rheology modifiers), antifoaming agents,antifreeze agents, pH adjusting agents, stabilizers, anticaking agentsand biocides (preservatives).

Possible surface-active substances are preferably anionic and nonionicsurfactants. Protective colloids are also suitable surface-activesubstances.

The quantity of surface-active substances will as a rule be 0.1 to 50wt. %, in particular 0.5 to 30 wt. %, based on the total weight of theplant protection agents according to the invention, or 0.5 to 100 wt. %,based on the total quantity of solid active substances in theformulation. Preferably, the surface-active substance include at leastone anionic surface-active substance and at least one nonionicsurface-active substance, and the proportion of anionic to nonionicsurface-active substance typically lies in the range from 10:1 to 1:10.

Surface-active compounds, also termed surfactants may be anionic,cationic, nonionic and amphoteric surfactants, block polymers,polyelectrolytes, and mixtures thereof. Such surfactants can be used asemulsifier, dispersant, solubilizer, wetter, penetration enhancer,protective colloid, or adjuvant. Examples of surfactants are listed inMcCutcheon's, Vol. 1: Emulsifiers & Detergents, McCutcheon'sDirectories, Glen Rock, USA, 2008 (International Ed. or North AmericanEd.).

Examples of anionic surfactants include alkyl aryl-sulfonates, aromaticsulfonates, for example ligninsulfonates (Borresperse types,Borregaard), phenylsulfonates, naphthalenesulfonates (Morwet types, AkzoNobel), dibutylnaphthalenesulfonates (Nekal types, BASF), alkylsulfates, in particular fatty alcohol sulfates, lauryl sulfates, andsulfated hexadeca-, heptadeca- and octadecanols, alkylsulfonates, alkylether sulfates, in particular fatty alcohol (poly)glycol ether sulfates,alkyl aryl ether sulfates, alkyl polyglycol ether phosphates,polyarylphenyl ether phosphates, alkyl-sulfosuccinates, olefinsulfonates, paraffin sulfon-ates, petroleum sulfonates, taurides,sarcosides, fatty acids, alkylnaphthalenesulfonic acids,naphthalene-sulfonic acids, ligninsulfonic acids, condensation productsof sulfonated naphthalenes with formaldehyde, condensation products ofsulfonated naphthalenes with formaldehyde and phenol and optionally ureaand condensation products of phenolsulfonic acid with formaldehyde andurea, lignin sulfite waste liquor, alkyl phosphates, alkyl arylphosphates, for example tristyryl phosphates, and polycarboxylates suchas for example polyacrylates, maleic anhydride/olefin copolymers (forexample Sokalan® CP9, BASF), including the alkali metal, alkaline earth,ammonium and amine salts of the aforesaid substances. Preferred anionicsurface-active substances are those which bear at least one sulfonategroup and in particular the alkali metal and ammonium salts thereof.

Examples of non-ionic surface-active substances are alkylphenolalkoxylates, in particular ethoxylates and ethoxylate-copropoxylates ofoctylphenol, isooctylphenol, nonylphenol and tributylphenol, di- andtristyrylphenol alkoxylates, alcohol alkoxylates, in particular fattyalcohol ethoxylates and fatty alcohol ethoxylate-copropoxylates, forexample alkoxylated isotridecanol, fatty amine alkoxylates,polyoxyethylene glycerol fatty acid esters, castor oil alkoxylates,fatty acid alkoxylates, fatty acid amide alkoxylates, fatty acidpolydiethanolamides, lanolin ethoxylates, fatty acid polyglycol esters,isotridecyl alcohol, ethoxylated fatty acid amides, ethoxylated fattyacid esters, alkyl polyglycosides, ethoxylated alkyl polyglycosides,sorbitan fatty acid esters, ethoxylated sorbitan fatty acid esters,glycerol fatty acid esters, lower molecular weight polyalkylene oxidessuch as polyethylene glycol, polypropylene oxide, polyethylene oxideco-propylene oxide di- and tri-block copolymers, and mixtures thereof.Preferred nonionic surface-active substances are fatty alcoholethoxylates, alkyl polyglycosides, glycerol fatty acid esters, castoroil ethoxylates, fatty acid ethoxylates, fatty acid amide ethoxylates,lanolin ethoxylates, fatty acid polyglycol esters, ethylene oxidepropylene oxide block copolymers and mixtures thereof.

Suitable cationic surfactants are quaternary surfactants, for examplequaternary ammonium compounds with one or two hydrophobic groups, orsalts of long-chain primary amines. Suitable amphoteric surfactants arealkylbetains and imidazolines. Suitable block polymers are blockpolymers of the A-B or A-B-A type comprising blocks of polyethyleneoxide and polypropylene oxide, or of the A-B—C type comprising alkanol,polyethylene oxide and polypropylene oxide. Suitable polyelectrolytesare polyacids or polybases. Examples of polyacids are alkali salts ofpolyacrylic acid or polyacid comb polymers. Examples of polybases arepolyvinylamines or polyethyleneamines.

Protective colloids are typically water-soluble, amphiphilic polymerswhich unlike the aforesaid surfactants typically have molecular weightsover 2,000 daltons (number average). Examples thereof are proteins anddenatured proteins such as casein, polysaccharides such as water-solublestarch derivatives and cellulose derivatives, hydrophobically modifiedstarches and celluloses, for example methylcellulose, and alsopolycarboxylates such as polyacrylic acid, acrylic acid copolymers andmaleic acid copolymers (BASF Sokalan types), polyvinyl alcohol (Mowioltypes from Clariant), polyalkoxylates, polyvinylpyrrolidone,vinylpyrrolidone copolymers, polyvinyl amines, polyethyleneimines(Lupasol types from BASF) and higher molecular weight polyalkyleneoxides such as polyethylene glycol, polypropylene oxides, andpolyethylene oxide copolypropylene oxide di- and tri-block copolymers.

The agrochemical compositions according to the invention can alsocontain one or more additives modifying the viscosity (rheologymodifiers). These are understood in particular to mean substances andsubstance mixtures which impart modified flow behavior to theformulation, for example a high viscosity in the resting state and lowviscosity in the moving state. The nature of the rheology modifier isdetermined by the nature of the formulation. As examples of rheologymodifiers, inorganic substances, for example layer silicates andorganically modified layer silicates such as bentonites or attapulgites(for example Attaclay®, Engelhardt Co.), and organic substances such aspolysaccharides and heteropolysaccharides such as Xanthan Gum® (Kelzan®from Kelco Co.), Rhodopol® 23 (Rhone Poulenc) or Veegum® (R.T.Vanderbilt Co.) should be mentioned. The quantity of theviscosity-modifying additives is often 0.1 to 5 wt. %, based on thetotal weight of the plant protection agent.

Examples of antifoaming agents are the silicone emulsions known for thispurpose (Silikon® SRE, Wacker Co. or Rhodorsil® from Rhodia Co.),long-chain alcohols, fatty acids and salts thereof, foam suppressants ofthe aqueous wax dispersion type, solid foam suppressants (so-calledCompounds) and organofluorine compounds and mixtures thereof. Thequantity of anti-foaming agent is typically 0.1 to 1 wt. %, based on thetotal weight of the plant protection agent.

The agrochemical compositions according to the invention may alsocontain preservatives for stabilization. Suitable preservatives arethose based on isothiazol-ones, for example Proxel® from ICI Co., orActicide® from Thor Chemie Co. or Kathon® MK from Rohm & Hass Co. Thequantity of preservative is typically 0.05 to 0.5 wt. %, based on thetotal weight of the SC.

Aqueous agrochemical compositions, i.e. those with an a aqueous carrier,often contain antifreeze agents. Suitable antifreeze agents are liquidpolyols, for example ethylene glycol, propylene glycol or glycerine, andurea. The quantity of antifreeze agent is as a rule 1 to 20 wt. %, inparticular 5 to 10 wt. %, based on the total weight of the aqueous plantprotection agent.

If the agrochemical composition, which contain the crystalline forms Aof compounds I.3 or I.5, respectively, are used for seed treatment, theycan also contain normal components such as are used for seed treatment,for example in dressing or coating. In addition to the aforesaidcomponents, these include in particular colorants, adhesives, fillersand plasticizers.

All the dyes and pigments usual for such purposes are possible ascolorants. Both pigments of low solubility in water and also dyessoluble in water are usable here. As examples, the dyes and pigmentsknown under the names Rhodamin B, C.I. Pigment Red 112 and C.I. SolventRed 1, Pigment Blue 15:4, Pigment Blue 15:3, Pigment Blue 15:2, PigmentBlue 15:1, Pigment Blue 80, Pigment Yellow 1, Pigment Yellow 13, PigmentRed 48:2, Pigment Red 48:1, Pigment Red 57:1, Pigment Red 53:1, PigmentOrange 43, Pigment Orange 34, Pigment Orange 5, Pigment Green 36,Pigment Green 7, Pigment White 6, Pigment Brown 25, Basic Violet 10,Basic Violet 49, Acid Red 51, Acid Red 52, Acid Red 14, Acid Blue 9,Acid Yellow 23, Basic Red 10, Basic Red 10 and Basic Red 108 may bementioned. The quantity of colorant will normally not constitute morethan 20 wt. % of the formulation and preferably lies in the range from0.1 to 15 wt. %, based on the total weight of the agrochemicalcomposition.

All binders normally usable in dressings come under consideration asadhesives. Examples of suitable binders include thermoplastic polymerssuch as poly-vinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol andtylose and also polyacrylates, polymethacrylates, polybutenes,polyisobutenes, polystyrene, polyethylene amines, polyethylene amides,the aforesaid protective colloids, polyesters, polyether esters,polyanhydrides, polyester urethanes, polyester amides, thermoplasticpolysaccharides, for example cellulose derivatives such as celluloseesters, cellulose ethers, cellulose ether esters, includingmethylcellulose, ethylcellulose, hydroxymethylcellulose,carboxymethylcellulose, hydroxypropyl cellulose and starch derivativesand modified starches, dextrins, maltodextrins, alginates and chitosans,and also fats, oils, proteins, including casein, gelatin and zein, gumArabic and shellac. The adhesives are preferably plant-compatible, i.e.they exhibit no, or no significant, phytotoxic effects. The adhesivesare preferably biodegradable. The adhesive is preferably selected suchthat it acts as a matrix for the active components of the formulation.The quantity of adhesive will normally not constitute more than 40 wt. %of the formulation and preferably lies in the range from 1 to 40 wt. %and in particular in the range from 5 to 30 wt. %, based on the totalweight of the agrochemical composition.

In addition to the adhesive, the agrochemical composition for seedtreatment can also contain inert fillers. Examples of these are theaforesaid solid carriers, in particular finely divided inorganicmaterials such as clays, chalk, bentonite, kaolin, talc, perlite, mica,silica gel, diatomaceous earth, quartz powder and montmorillonite butalso fine-particle organic materials such as wood flour, cereal flour,active charcoal and the like. The quantity of filler is preferablyselected such that the total quantity of filler does not exceed 70 wt.%, based on the total weight of all non-volatile components of theformulation. Often, the quantity of filler lies in the range from 1 to50 wt. %, based on the total weight of all non-volatile components ofthe agrochemical composition.

In addition, the agrochemical composition for seed treatment can alsocontain a plasticizer which increases the flexibility of the coating.Examples of plasticizers are oligomeric polyalkylene glycols, glycerine,dialkyl phthalates, alkylbenzyl phthalates, glycol benzoates andcomparable compounds. The quantity of plasticizer in the coating oftenlies in the range from 0.1 to 20 wt. %, based on the total weight of allnon-volatile components of the agrochemical composition.

A preferred embodiment of the invention relates to liquid formulationsof the forms A of compounds I.3 or I.5, respecitvely. In addition to thesolid active substance phase, these have at least one liquid phase, inwhich form A of compound I.3 and form A of compound I.5, respectively,are present in the form of dispersed particles. Possible liquid phasesare essentially water and those organic solvents in which the forms A ofcompounds I.3 or I.5, respectively, are only slightly soluble, orinsoluble, for example those wherein the solubilities of forms A ofcompounds I.3 or I.5, respectively, at 25° C. and 1013 mbar are not morethan 1 wt. %, in particular not more than 0.1 wt. %, and especially notmore than 0.01 wt. %.

According to a first preferred embodiment, the liquid phase is selectedfrom water and aqueous solvents, i.e. solvent mixtures which in additionto water also contain up to 20 wt. %, preferably however not more than10 wt. %, based on the total quantity of water and solvent, of one ormore organic solvents miscible with water, for example ethers misciblewith water such as tetrahydrofuran, methyl glycol, methyl diglycol,alkanols such as isopropanol or polyols such as glycol, glycerine,diethylene glycol, propylene glycol and the like. Such formulations arealso referred to below as suspension concentrates (SCs).

Such suspension concentrates contain compound I.3 as form A or compoundI.5 as form A in a particulate form, wherein the particles of the formsA are present suspended in an aqueous phase. The size of the activesubstance particles, i.e. the size which 90 wt. % of the activesubstance particles do not exceed, here typically lies below 30 μm, inparticular below 20 μm. Advantageously, in the SCs according to theinvention, at least 40 wt. % and in particular at least 60 wt. % of theparticles have diameters below 2 μm.

In such SCs the quantity of active substance, i.e. the total quantity oftembotrione and of other active substances if necessary, usually lies inthe range from 5 to 70 wt. %, in particular in the range from 10 to 50wt. %, based on the total weight of the suspension concentrate.

In addition to the active substance, aqueous suspension concentratestypically contain surface-active substances, and also if necessaryantifoaming agents, thickeners (=rheology modifiers), antifreeze agents,stabilizers (biocides), agents for adjusting the pH and anticakingagents.

Possible surface-active substances are the previously namedsurface-active substances. Preferably the aqueous plant protectionagents according to the invention contain at least one of the previouslynamed anionic surfactants and if necessary one or more nonionicsurfactants, if necessary in combination with a protective colloid. Thequantity of surface-active substances will as a rule be 1 to 50 wt. %,in particular 2 to 30 wt. %, based on the total weight of the aqueousSCs according to the invention. Preferably the surface-active substancesinclude at least one anionic surface-active substance and at least onenonionic surface-active substance, and the proportion of anionic tononionic surface-active substance typically lies in the range from 10:1to 1:10.

Concerning the nature and quantity of the antifoaming agents,thickeners, antifreeze agents and biocides, the same applies asaforesaid.

If necessary, the aqueous SCs according to the invention can containbuffers for pH regulation. Examples of buffers are alkali metal salts ofweak inorganic or organic acids, such as for example phosphoric acid,boric acid, acetic acid, propionic acid, citric acid, fumaric acid,tartaric acid, oxalic acid and succinic acid.

According to a second preferred embodiment, the liquid phase consists ofnon-aqueous organic solvents in which the solubility of form A ofcompound I.3 and of form A of compound I.5, respectively, at 25° C. and1013 mbar is not more than 1 wt. %, in particular not more than 0.1 wt.%, and especially not more than 0.01 wt. %. These include in particularaliphatic and cycloaliphatic hydrocarbons and oils, in particular thoseof plant origin, and also C₁-C₄ alkyl esters of saturated or unsaturatedfatty acids or fatty acid mixtures, in particular the methyl esters, forexample methyl oleate, methyl stearate and rape oil methyl ester, butalso paraffinic mineral oils and the like. Accordingly, the presentinvention relates also to agents for plant protection in the form of anon-aqueous suspension concentrate, which will also be referred to belowas OD (oildispersion). Such ODs contain the forms A of compounds I.3 orI.5, respectively, in particulate form, wherein the particles of forms Aof compounds I.3 or I.5, respectively, are present suspended in anon-aqueous phase. The size of the active substance particles, i.e. thesize which 90 wt. % of the active substance particles do not exceed,here typically lies below 30 μm, in particular below 20 μm.Advantageously, in the non-aqueous suspension concentrates, at least 40wt. % and in particular at least 60 wt. % of the particles havediameters below 2 μm.

In such ODs, the quantity of active substance, i.e. the total quantityof compound I.3 or I.5 and of other active substances if necessary,usually lies in the range from 10 to 70 wt. %, in particular in therange from 20 to 50 wt. %, based on the total weight of the non-aqueoussuspension concentrate.

In addition to the active substance and the liquid carrier, non-aqueoussuspension concentrates typically contain surface-active substances, andalso if necessary antifoaming agents, agents to modify the rheology andstabilizers (biocides).

Possible surface-active substances are preferably the previously namedanionic and nonionic surfactants. The quantity of surface-activesubstances will as a rule be 1 to 30 wt. %, in particular 2 to 20 wt. %,based on the total weight of the non-aqueous SCs according to theinvention. Preferably the surface-active substances include at least oneanionic surface-active substance and at least one nonionicsurface-active substance, and the proportion of anionic to nonionicsurface-active substance typically lies in the range from 10:1 to 1:10.

Forms A of compounds I.3 or I.5, respectively, can also be formulated assolid plant protection agents. These include powder, scattering anddusting agents but also water-dispersible powders and granules, forexample coated, impregnated and homogenous granules. Such formulationscan be produced by mixing or simultaneous grinding of either form A ofcompound I.3 or form A of compound I.5, respectively, with a solidcarrier and if necessary other additives, in particular surface-activesubstances. Granules can be produced by binding of the active substancesto solid carriers. Solid carriers are mineral earths such as silicicacids, silica gels, silicates, talc, kaolin, limestone, lime, chalk,bole, loess, clay, dolomite, diatomaceous earth, calcium and magnesiumsulfate, magnesium oxide, ground plastics, fertilizers such as ammoniumsulfate, ammonium phosphate, ammonium nitrate, ureas and plant productssuch as cereal flour, tree bark, wood and nutshell flour, cellulosepowder or other solid carriers. Solid formulations can also be producedby spray drying, if necessary in the presence of polymeric or inorganicdrying aids, and if necessary in the presence of solid carriers. For theproduction of solid formulations of forms A of compounds I.3 or I.5,respectively, extrusion processes, fluidized bed granulation, spraygranulation and comparable technologies are suitable.

Possible surface-active substances are the previously named surfactantsand protective colloids. The quantity of surface-active substances willas a rule be 1 to 30 wt. %, in particular 2 to 20 wt. %, based on thetotal weight of the solid formulation according to the invention.

In such solid formulations, the quantity of active substance, i.e. thetotal quantity of tembotrione and of other active substances ifnecessary, usually lies in the range from 10 to 70 wt. %, in particularin the range from 20 to 50 wt. %, based on the total weight of the solidformulation.

The following formulation examples illustrate the production of suchpreparations:

-   I. Water-dispersible powder:    -   20 parts by weight of forms A of compounds I.3 or I.5,        respectively, are mixed well with 3 parts by weight of the        sodium salt of diisobutylnaphthalenesulfonic acid, 17 parts by        weight of the sodium salt of a ligninsulfonic acid from a        sulfite waste liquor and 60 parts by weight of powdered silica        gel and ground in a hammer mill. In this manner, a        water-dispersible powder which contains the respective form A is        obtained.-   II. Dusting agent    -   5 parts by weight of the forms A of compounds I.3 or I.5,        respectively, are mixed with 95 parts by weight of finely        divided kaolin. In this manner, a dusting agent which contains 5        wt. % of the respective form A is obtained.-   III. Non-aqueous suspension concentrate:    -   20 parts by weight of forms A of compounds I.3 or I.5,        respectively, are mixed intimately with 2 parts by weight of the        calcium salt of dodecylbenzenesulfonic acid, 8 parts by weight        of fatty alcohol polyglycol ether, 2 parts by weight of the        sodium salt of a phenolsulfonic acid urea formaldehyde        condensate and 68 parts by weight of a paraffinic mineral oil. A        stable, non-aqueous suspension concentrate of the respective        form A is obtained.-   IV. Non-aqueous suspension concentrate:    -   20 parts by weight of forms A of compounds I.3 or I.5,        respectively, are ground to a fine active substance suspension        in an agitator ball mill with the addition of 10 parts by weight        of dispersants and wetting agents and 70 parts by weight of a        paraffinic mineral oil. A stable, non-aqueous suspension        concentrate of the respective form A is obtained. On dilution in        water, a stable suspension of the respective form A is obtained.        The active substance content in the formulation is 20 wt. %.-   V. Aqueous suspension concentrate:    -   10 parts by weight of forms A of compounds I.3 or I.5,        respectively, are formulated as an aqueous suspension        concentrate in a solution of 17 parts by weight of a        poly(ethylene glycol)(propylene glycol) block copolymer, 2 parts        by weight of a phenolsulfonic acid formaldehyde condensate and        about 1 part by weight of other additives (thickeners, foam        suppressants) in a mixture of 7 parts by weight of propylene        glycol and 63 parts by weight of water.-   VI. Aqueous suspension concentrate:    -   20 parts by weight of forms A of compounds I.3 or I.5,        respectively, are ground to a fine active substance suspension        in a stirred ball mill with the addition of 10 parts by weight        of dispersants and wetting agents and 70 parts by weight of        water. On dilution in water, a stable suspension of the        respective form A is obtained. The active substance content in        the formulation is 20 wt. %.-   VII. Water-dispersible and water-soluble granules    -   50 parts by weight of forms A of compounds I.3 or I.5,        respectively, are finely ground with the addition of 50 parts by        weight of dispersants and wetting agents and formulated as        water-dispersible or water-soluble granules by means of        industrial devices (for example extrusion, spray tower,        fluidized bed). On dilution in water, a stable dispersion or        solution of the respective form A is obtained. The formulation        has an active substance content of 50 wt. %.-   VIII. Water-dispersible and water-soluble powder    -   75 parts by weight of forms A of compounds I.3 or I.5,        respectively, are ground in a rotorstator mill with the addition        of 25 parts by weight of dispersants and wetting agents and also        silica gel. On dilution in water, a stable dispersion or        solution of the respective form A is obtained. The active        substance content of the formulation is 75 wt. %.-   IX. Gel formulations:    -   20 parts by weight of forms A of compounds I.3 or I.5,        respectively, 10 parts by weight of dispersant, 1 part by weight        of gelling agent and 70 parts by weight of water or an organic        solvent are ground to a fine suspension in a ball mill. On        dilution in water, a stable suspension of the respective form A        is obtained. The active substance content of the formulation is        20 wt. %.-   X. Directly usable granules (GR, FG, GG, MG)    -   0.5 parts by weight of the forms A of compounds I.3 or I.5,        respectively, are finely ground and combined with 99.5 parts by        weight of carriers. Common processes here are extrusion, spray        drying or fluidized bed. Granules for direct application with        0.5 wt. % active substance content are thus obtained.

The application of forms A of compounds I.3 or I.5, respectively, or theagrochemical composition containing them is effected, if the formulationis not already ready for use, in the form of aqueous spray fluids. Theseare prepared by dilution of the aforesaid compositions containing formsA of compounds I.3 or I.5, respectively, with water. The spray fluidscan also contain other components in dissolved, emulsified or suspendedform, for example fertilizers, active substances of other herbicidal orgrowth-regulating active substance groups, other active substances, forexample active substances for combating animal pests or phyto-pathogenicfungi or bacteria, and also mineral salts which are used for theelimination of nutritional and trace element deficiencies, andnon-phytotoxic oils and oil concentrates. As a rule, these componentsare added to the spray fluid before, during or after the dilution of theformulations according to the invention. The user applies thecomposition according to the invention usually from a predosage device,a knapsack sprayer, a spray tank, a spray plane, or an irrigationsystem. Usually, the agrochemical composition is made up with water,buffer, and/or further auxiliaries to the desired applicationconcentration and the ready-to-use spray liquor or the agrochemicalcomposition according to the invention is thus obtained. Usually, 20 to2000 liters, preferably 50 to 400 liters, of the ready-to-use sprayliquor are applied per hectare of agricultural useful area.

When employed in plant protection, the amounts of compounds I.3 or I.5applied are, depending on the kind of effect desired, from 0.001 to 2 kgper ha, preferably from 0.005 to 2 kg per ha, more preferably from 0.05to 0.9 kg per ha, and in particular from 0.1 to 0.75 kg per ha.

In treatment of plant propagation materials such as seeds, e. g. bydusting, coating or drenching seed, amounts of compounds I.3 or I.5 offrom 0.1 to 1000 g, preferably from 1 to 1000 g, more preferably from 1to 100 g and most preferably from 5 to 100 g, per 100 kilogram of plantpropagation material (preferably seeds) are generally required.

When used in the protection of materials or stored products, the amountsof compounds I.3 or I.5 applied depends on the kind of application areaand on the desired effect. Amounts customarily applied in the protectionof materials are 0.001 g to 2 kg, preferably 0.005 g to 1 kg, of activesubstance per cubic meter of treated material.

Various types of oils, wetters, adjuvants, fertilizer, ormicronutrients, and further pesticides (e.g. herbicides, insecticides,fungicides, growth regulators, safeners, biopesticides) may be added tothe active substances or the compositions comprising them as premix or,if appropriate not until immediately prior to use (tank mix). Theseagents can be admixed with the compositions according to the inventionin a weight ratio of 1:100 to 100:1, preferably 1:10 to 10:1.

EXAMPLES AND FIGURES

The following figures and examples further illustrate the presentinvention and do not restrict the invention in any manner.

FIG. 1 shows an X-ray powder diffraction diagram of form A of compoundI.3.

FIG. 2 shows an X-ray powder diffraction diagram of form A of compoundI.5.

ANALYTICS

The X-ray powder diffractogramm of forms A and B were recorded with aPanalytical X'Pert Pro diffractometer in reflection geometry in therange from 2θ=3°-35° with a step width of 0.0167° using Cu-Kα radiation(1.54178 Å) at 25° C. The recorded 2θ valuese were used to calculate thed values. The intensity of the peaks (linear intensity counts) isplotted versus 2θ angel (x axis in °2θ).

Single crystal X-ray diffraction data were collected at 100 K on aBruker AXS CCD Detector, using graphite-monochromated CuKα radiation(λ=1.54178 Å). The structure was solved with direct methods, refined,and expanded by using Fourier techniques with the SHELX software package(G.M. Sheldrick, SHELX-97, University of Gottingen 1997). Absorbtioncorrection was performed with SADABS software.

DSC was performed on a Mettler Toledo DSC 823e module. The sample wasplaced in crimped but vented aluminium pans. Sample size was 3 mg. Thethermal behaviour was analysed in the range 30-200° C. by using aheating rate of 10° C./min and a nitrogen stream of 150 mL/min.

Melting point values and polymorphic transitions were confirmed by aMettler Hot Stage in combination with a light microscope.

A) Preparation of Reagent IV

Example A1

Preparation of an aqueous trimethylsulfonium-methylsulfate solution(11.3 wt-% water)

304 g dimethylsulfide and 30 g water (1.67 mole) were stirred at 25° C.Then, 146 g dimethylsulfate (1.15 mole) were added over 60 min, whereinthe temperature increased to up to 35° C. Then, it was stirred 2 h at 35to 38° C. In order to achieve phase separation, it was cooled to 30° C.and not stirred. 246 g of the lower aqueous phase were obtained.

The water content of the solution was measure by means ofKarl-Fischer-titration and was 11.3 wt-%. The content oftrimethylsulfonium-methylsulfate was quantified to be 85.3 wt-%;(SMe₃)⁺: 35 wt-% (quant.-NMR in D₂O, di-Na-salt of fumaric acid asinternal standard). The viscosity of the solution at 25° C. was 18.3mPa*s.

Characterization: ¹H-NMR (400 MHz, D2O): δ/ppm=2.9 (s, 9H), 3.72 (s,3H), 4.66 (s, H₂O).

Example A2

Preparation of an aqueous trimethylsulfonium-methylsulfate solution(14.9 wt-% water)

304 g dimethylsulfide and 41.3 g water (2.3 mole) were stirred at 25° C.Then, 146 g dimethylsulfate (1.15 mole) were added over 60 min, whereinthe temperature increased to up to 35° C. Then, it was stirred 2 h at 35to 38° C. In order to achieve phase separation, it was cooled to 30° C.and not stirred. 259 g of the lower aqueous phase were obtained.

The water content of the solution was measure by means ofKarl-Fischer-titration and was 14.9 wt-%. The content oftrimethylsulfonium-methylsulfate was quantified to be 83.2 wt-%;(SMe₃)⁺: 34 wt-% (quant.-NMR in D₂O, di-Na-salt of fumaric acid asinternal standard). The viscosity of the solution at 25° C. was 12.5mPa*s.

Example A3

Preparation of an aqueous trimethylsulfonium-methylsulfate solution(11.2 wt-% water)

144 g dimethylsulfide, 30 g water (1.67 mole) and 236 g toluol werestirred at 25° C. Then, 146 g dimethylsulfate (1.15 mole) were addedover 60 min, wherein the temperature increased to up to 46° C. Then, itwas stirred 2 h at 30° C. In order to achieve phase separation, it wascooled to 30° C. and not stirred. 245 g of the lower aqueous phase wereobtained.

The water content of the solution was measure by means ofKarl-Fischer-titration and was 11.2 wt-%. The content oftrimethylsulfonium-methylsulfate was quantified to be 84.5 wt-%;(SMe₃)⁺: 34.8 wt-% (quant.-NMR in D₂O, di-Na-salt of fumaric acid asinternal standard).

Comparative Example

Preparation of an aqueous trimethylsulfonium-methylsulfate solution (6.5wt-% water)

304 g dimethylsulfide and 15.0 g water (0.83 mole) were stirred at 25°C. Then, 146 g dimethylsulfate (1.15 mole) were added over 60 min,wherein the temperature was at most 35° C. Then, it was stirred for 2 hat 35 to 38° C. In order to achieve phase separation, it was cooled to30° C. and not stirred. 237 g of the lower aqueous phase were obtained.

The water content of the solution was measured by means ofKarl-Fischer-titration and was 6.5 wt-%. The content oftrimethylsulfonium-methylsulfate was quantified to be 89.6 wt-%;(SMe₃)⁺: 37.2 wt-% (quant.-NMR in D₂O, di-Na-salt of fumaric acid asinternal standard). The viscosity of the solution at 30° C. was 35.1mPa*s. The solution was not stable at 25° C. Long specular crystals wereformed.

B) Synthesis of Oxiranes

Example B1 Synthesis of2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane

1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]ethanone (0.87 mole)dissolved in 372 g dimethylsulfide together with 250 g aqueoustrimethylsulfonium-methylsulfate (86 wt-%, prepared according to ExampleA1) were provided at 23° C. 15 g KOH pellets, 85 wt-% (0.265 mole), wereadded while stirring heavily. This led to an increase of temperature ofabout 5° C. Then, it was continued stirring for 10 h at 38° C. A sampleof the reaction mixture showed full conversion of the ketone (HPLC).After that, 1350 g 20 wt-% NaCl solution was added at 30° C. Afterseparation of the aqueous phase, the dimethylsulfide-solution wasconcentrated by means of distillation of the solvent at a temperature ofup to 98° C. 324 g2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxiranehaving about 90 wt-% (quant. HPLC) were obtained; yield > 99%.

Characterisation

A sample oft the raw product was dissolved at 40° C. in diisopropyletherand cooled down to −5° C. The product was obtained as crystallinecompound. Melting point: 60° C.

¹H-NMR (400 MHz, CDCl3): δ/ppm=1.63 (s, 3H), 2.92 (d, 1H), 3.02 (d, 1H),6.95 (d, 2H), 7.13 (m, 1H), 7.22 (s, 1H), 7.34 (d, 2H) 7.64 (d, 1H);

¹³C-NMR (125 MHz, CDCl3): δ/ppm=24.82 (q), 55.41 (t), 57.27 (s), 115.94(d), 120.63 (d, 2C) 121.48 (d), 123.91 (s), 128.60 (s), 129.36 (s),130.05 (d, 2C), 131.04 (d), 134.59 (s), 154.50 (s), 156.56 (s)

Example B2 Synthesis of2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-cyclopropyl-oxirane

1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]cyclopropyl-methanone(0.80 mole) dissolved in 343 g dimethylsulfide together with 263.4 gaqueous trimethylsulfonium-methylsulfate (86 wt-%, prepared according toExample A1) were provided at 23° C. 212 g KOH pellets, 85 wt-% (3.21mole), were added while stirring heavily. This led to an increase oftemperature of about 5° C. to 7° C. Then, it was continued stirring for8 h at 38° C. A sample of the reaction mixture showed full conversion ofthe ketone (HPLC). After that, 1236 g 20 wt-% Ige NaCl solution wasadded at 30° C. After separation of the aqueous phase, thedimethylsulfide-solution was concentrated by means of distillation ofthe solvent at a temperature of up to 90° C. 332 g of 82 wt-%-product(quant. HPLC)(2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-cyclopropyl-oxirane)were obtained; yield >95%.

Characterisation

A sample oft the raw product was dissolved at 60° C. in isopropanole andcooled down to 10° C. The product was obtained as crystalline compound.Melting point: 45° C.

¹³C-NMR (125 MHz, CDCl3): δ/ppm=1.06 (t), 2.17 (t), 15.87 (d), 53.09(t), 58.46 (s), 115.47 (d), 121.20 (d, 2C) 121.65 (d), 124.01 (s),127.59 (s), 128.4 (s), 130.16 (d, 2C), 132.10 (d), 133.52 (s), 154.26(s), 156.27 (s)

Example B3 Synthesis of2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-isopropyl-oxirane

1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-propan-1-one(0.078 mole) dissolved in 62 g dimethylsulfide together with 22.2 gaqueous trimethylsulfonium-methylsulfate (80 wt-%, prepared according toExample A1) were provided at 27° C. 15.4 g KOH pellets, 85 wt-% (0.23mole), were added while stirring heavily. This led to an increase oftemperature of about 5° C. to 7° C. Then, it was continued stirring for3.5 h at 38° C. A sample of the reaction mixture showed full conversionof the ketone (HPLC). After that, 45 g water were added at 25° C. Afterseparation of the aqueous phase, the dimethylsulfide-solution wasdiluted with a little toluol and washed again with 105 g water. Then,the organic phase was concentrated by means of distillation of thesolvent at 50° C. and up to a pressure of 2 mbar. 30 g of about 81%(area-% HPLC)2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-isopropyl-oxiranewere obtained; yield about 88%.

Characterization:

A sample of the raw product was analyzed by means of NMR spectroscopy.

¹³C-NMR (125 MHz, CDCl3): δ/ppm=17.32 (q), 17.55 (q), 31.57 (d), 52.93(t), 62.71 (s), 116.28 (d), 120.73 (d, 2C) 121.69 (d), 123.95 (s),127.41 (s), 129.41 (s), 130.12 (d, 2C), 131.97 (d), 134.12 (s), 154.67(s), 156.56 (s)

¹H-NMR (400 MHz, CDCl3): δ/ppm=0.85-0.95 (dd, 6H), 2.22-2.35 (md, 1H),2.78 (d, 1H), 3.20 (d, 1H), 6.98 (d, 2H), 7.10 (m, 1H), 7.23 (s, 1H),7.35 (d, 2H) 7.55 (d, 1H)

Example B4 Synthesis of2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane

1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]ethanone (0.13 mole)dissolved in 55 g dimethylsulfide together with 45 g aqueoustrimethylsulfonium-methylsulfate (80 wt-%, 17 wt-% H₂O), preparedaccording to Example A2), were provided at 23° C. 25 g KOH pellets, 85wt-% (0.38 mole), were added while stirring heavily. This led to anincrease of temperature of about 5° C. Then, it was continued stirringfor 8 h at 38° C. A sample of the reaction mixture showed fullconversion of the ketone (HPLC). After that, 199 g 20 wt-% NaCl solutionwas added at 30° C. After separation of the aqueous phase, thedimethylsulfide-solution was concentrated by means of distillation ofthe solvent at a temperature of up to 90° C. 56 g of 77 wt-% (quant.HPLC) 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxiranewere obtained; yield >95%.

Example B5 Synthesis of2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane

1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]ethanone (0.45 mole)dissolved in 280 g toluol together with 129 g aqueoustrimethylsulfonium-methylsulfate (86 wt-%), prepared according toExample A1, were provided at 24° C. 89 g KOH pellets, 85 wt-% (0.38mole) were added while stirring heavily. This led to an increase oftemperature of about 4° C. Then, it was continued stirring for 21 h at38° C. A sample of the reaction mixture showed full conversion of theketone (HPLC). After that, 500 g 20 wt-% 20 wt-% NaCl solution was addedat 30° C. After separation of the aqueous phase, the toluol solution wasconcentrated by means of distillation of the solvent at a temperature ofup to 98° C. and a pressure of 50 mbar. 163 g of about 89 wt-% (quant.HPLC)2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-cyclopropyl-oxiranewere obtained; yield >95%.

Example B6 Synthesis of2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane

1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]ethanone (0.128 mole)dissolved in 55.4 g dimethylsulfide were provided at 22° C. 25.4 g KOHpellets, 85 wt-% (0.385 mole) were added while stirring heavily. Then,42.1 g aqueous trimethylsulfonium-methylsulfate (85.6 wt-%, preparedaccording to Example A1) were added. This led to an increase oftemperature of about 2 to 3° C. Then, it was continued stirring for 8 hat 38° C. A sample of the reaction mixture showed full conversion of theketone (HPLC). After that, 199 g 20 wt-% Ige 20 wt-% NaCl solution wasadded at 30° C. After separation of the aqueous phase, thedimethylsulfide solution was concentrated by means of distillation ofthe solvent at a temperature of up to 90° C. 49.7 g of about 82 wt-%(quant. HPLC)2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane wereobtained; yield about 97%.

Example B7 Synthesis of2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-cyclopropyl-oxirane

1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]cyclopropyl-methanone(0.122 mole) dissolved in 52 g dimethylsulfide were provided at 22° C.32.2 g KOH pellets, 85 wt-% (0.488 mole), were added while stirringheavily. Then, 40.1 g aqueous trimethylsulfonium-methylsulfate (85.6wt-%, prepared according to Example A1) were added. This led to anincrease of temperature of about 3 to 5° C. Then, it was continuedstirring for 8 h at 38° C. A sample of the reaction mixture showed fullconversion of the ketone (HPLC). After that, 187 g 20 wt-% ige 20 wt-%NaCl solution was added at 30° C. After separation of the aqueous phase,the dimethylsulfide solution was concentrated by means of distillationof the solvent at a temperature of up to 90° C. 50.0 g, about 82 wt-%(quant. HPLC)2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane wereobtained; yield about 91%.

C) Synthesis of Triazoles

Example C12-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-(1,2,4-triazol-1-yl)propan-2-ol(compound I.3)

235.3 g (95.4 wt-%; 0.683 mole)2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane wereprovided in 496 g DMF and heated to 60° C. Then, one after the other,60.6 g (99 wt-%; 0.869 mole) of triazole and 13.4 g (0.335 mole)NaOH-powder were added under stirring. The reaction mixture was heatedto 125° C. and then stirred for 4 h in total at this temperature. AHPLC-sample showed almost complete conversion to the desired product(ratio triazol-1-yl/triazol-4-yl about 10:1). About 80% of the DMF wasevaporated at 65° C./4 mbar. To the concentrated reaction mixture, 714 gtoluol and 400 g water were added. Then, the aqueous phase was separatedat 60° C. The toluol phase was washed again with 200 g water. Theaqueous phase was separated and the toluol solution was concentrated at70° C./50 mbar to a solution containing about 50% of the product.Precipitated solids were re-dissolved by heating to 80° C. The solutionwas cooled down from 80° C. to 0° C. with a rate of 5° K/h understirring. The suspension of solids was easily stirrable and wasseparated by suction filtration and washed 2 times with 2×100 g freshand cold toluol. The solid compound was dried at 25° C./50 mbar.

Yield: 456 g (98 wt-%; triazol-4-yl-Isomer: not detectable); 82% of thetheory.

Melting point: 126 to 127° C.

The thus obtained crystalline material was analyzed by means of DSC andby means of X-ray powder diffractometry (XRPD). The X-ray powderdiffractogram is depicted in FIG. 1. The reflections are summarized intable 1.

¹H-NMR (400 MHz, CDCl₃): δ/ppm=1.64 (s, 3H), 4.55 (s, OH), 4.44 (d, 1H),4.62 (d, 1H), 6.92-7.61 (m, 7H), 7.87 (s, 1H), 8.02 (s, 1H)

¹³C-NMR (125 MHz, CDCl₃): δ/ppm=27.8 (q), 59.02 (t), 74.77 (s), 118.21(d), 120.50 (d), 120.82 (d, 2C), 123.95 (CF3), 128.96 (s), 129.54 (s),130.09 (d, 2C), 130.42 (d), 137.30 (s), 144.34 (d), 151.46 (d), 154.24(s), 156.49 (s)

Single crystals of form A of compound I.3 were obtained by evaporationfrom a solution of the title compound in acetonitrile at ambienttemperature. Single crystal X-ray diffraction data were collected asdescribed above and the crystallographic parameters were calculatedtherefrom. The thus calculated crystallographic parameters aresummarized in table 2.

Example C21-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-cyclopropyl-2-(1,2,4-triazol-1-yl)ethanol

12.8 g (98 wt-%; 0.182 mole) triazole and 2.86 g (0.07 mole) NaOH powderwere added to 217.5 of a 22.8 wt-% DM F-solution of2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-cyclopropyl-oxirane(0.14 mole) at 25° C. After heating to 125° C. the reaction mixture wasstirred at this temperature for 10 h in total. A HPLC-sample showedalmost complete conversion to the desired product (ratiotriazol-1-yl/triazol-4-yl about 7.3:1). About 90% of the DMF wasevaporated at 125° C./60 mbar. To the concentrated reaction mixture, 140g toluole and 86 g water were added at 40° C. Then, the aqueous phasewas separated at 80° C. The toluene solution was concentrated up to 86°C./40 mbar. About 133 g of distillate were obtained. The residue wascooled to 60° C. and 25 g methanol were added. After cooling to 45° C.,seed crystals were added and the reaction mixture was held at 45° C. for30 min. Then, the mixture was cooled to 0° C. within 5 h and stirred for12 h. The suspension of solids was easily stirrable and was separated bysuction filtration and washed 1 time with 21 g methanol of a temperatureof 0° C. The solid compound was dried at 55° C. and 15 mbar.

Yield: 42.4 g (94.6 wt-%; about 3 wt-% MeOH; ratiotriazole-1-yl/triazole-4-yl about 39:1); 68% of the theory.

Melting point: 86 to 87° C.

¹H-NMR (400 MHz, CDCl₃): δ/ppm=0.28-0.42 (m, 4H), 1.38-1.43 (m, 1H),4.2-4.4 (s, breit, OH), 4.49 (d, 1H), 4.76 (d, 1H), 6.92-7.76 (m, 7H),7.92 (s, 1H), 8.0 (s, 1H)

¹³C-NMR (125 MHz, CDCl₃): δ/ppm=−0.12 (t), 1.61 (t), 18.91 (d), 58.78(t), 75.09 (s), 118.14 (d), 120.34 (d), 120.9 (d, 2C), 123.97 (CF3),129.20 (s), 129.53 (s), 130.08 (d, 2C), 130.92 (d), 137.06 (s), 144.18(d), 151.84 (d), 154.24 (s), 156.44 (s)

Example C2a crystallization of1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-cyclopropyl-2-(1,2,4-triazol-1-yl)ethanol

206.5 g of a toluene solution of1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-cyclopropyl-2-(1,2,4-triazol-1-yl)ethanol(41.8 wt-%; 0.204 mol) prepared as described in example C2 wereconcentrated up to 60° C./10 mbar. The residue was cooled to 50° C. anddissolved in mixture of 50 g ethanole and 9 g water. After cooling to30° C., seed crystals are added and the reaction mixture was held at 30°C. for 60 min. Then, the mixture was cooled to 0° C. with a rate of 2.5°K/min 5 h and stirred for at 0° C. for 4 days. The suspension of solidswas easily stirrable and was separated by suction filtration and washed1 time with 39 g ethanole of a temperature of 0° C. The solid compoundwas dried at 60° C./10 mbar.

76.4 g (93.7 wt-%; ratio triazole-1-yl/triazole-4-yl about 44:1)colourless crystals containing ethanole in a molar ratio relative to theproduct of about 1/3 (detected by ¹H-NMR spectroscopy) were obtained;83% crystallization yield.

Melting point: 81.5° C.

Example C32-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-3-methyl-1-(1,2,4-triazol-1-yl)butan-2-ol(compound I.5)

2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-isopropyl-oxirane(92.9 g, 76.9 wt-%, 0.217 mole) were dissolved in 180.6 g DMF. To thissolution, 27.4 g (98 wt-%; 0.391 mole) triazole and 4.7 g (0.117 mole)NaOH powder were added at 25° C. After heating to 125° C. the reactionmixture was stirred at this temperature for 22.5 h in total. AHPLC-sample showed still remaining oxirane and a ratio of the triazoleproducts of 10.3:1 (triazole-1-yl/triazole-4-yl). The addition ofadditional 0.3 eq triazole and stirring for another 2 h at 125° C. didnot improve the conversion. About 79% of the DMF were evaporated at upto 60° C./4 mbar. 413 g toluole and 205 g water were added to theconcentrated reaction mixture at 80° C. Then, the aqueous phase wasseparated at 55° C. The toluol solution was concentrated at up to 90°C./40 mbar until a residue of 108 g remained. 111 g methanol were addedto the residue at 60° C. The solution obtained was cooled down to −1° C.with a rate of 5° C./h. Seed crystals were added at 45° C. Thesuspension of solids was easily stirrable and was separated by suctionfiltration and washed 1 time with 25 g of fresh and cold (0° C.)methanol. The solid compound was dried at 55° C. and 50 mbar.

Yield: 64.8 g (96.9 wt-%; ratio triazole-1-yl/triazole-4-yl about100:1); 73% of the theory. The crystals contained residual methanol asdetected be ¹H-NMR

Melting point: 114 to 115° C.

¹H-NMR (400 MHz, CDCl₃): δ/ppm=0.87 (d, 3H), 1.2 (d, 3H), 2.38 (m, 1H),4.3-4.65 (s, breit, OH), 4.58 (d, 1H), 4.75 (d, 1H), 6.85-7.54 (m, 7H),7.7 (s, 1H), 7.8 (s, 1H)

¹³C-NMR (125 MHz, CDCl₃): δ/ppm=16.83 (q), 17.44 (q), 37.00 (d), 57.70(t), 80.43 (s), 117.98 (d), 120.13 (d), 120.87 (d, 2C), 123.75 (CF3),129.54 (s), 130.10 (d, 2C), 130.20 (d), 130.82 (s), 136.65 (s), 143.83(d), 151.69 (d), 154.20 (s), 156.06 (s)

Example C42-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-3-methyl-1-(1,2,4-triazol-1-yl)butan-2-ol(compound I.5)

Preparation of compound I.5 was performed as described for experimentC.3, except that no seed crystals were added at 45° C. during cooling ofthe solution of compound I.5 in methanol. The thus obtained crystallinematerial was analyzed by means of DSC and by means of X-ray powderdiffractometry (XRPD). The X-ray powder diffractogram is depicted inFIG. 2. The reflections are summarized in table 3.

Single crystals of form A of compound I.5 were obtained by dissolvingthus obtained compound I.5 in 3-propanol and allowing heptane to diffuseinto this solution at ambient temperature. Single crystal X-raydiffraction data were collected as described above and thecrystallographic parameters were calculated therefrom. The thuscalculated crystallographic parameters are summarized in table 4.

D) Comparison Examples for the Amount of Base Used:

The base and the triazole in the amounts detailed in the table D belowwere added to a 20-25% solution of the respective oxirane II in DMF. At125° C., the product of formula I was obtained. After evaporation of themajor amount of DMF, the residue was partioned between toluole andwater. The yield was determined after azeotropic drying andconcentration by means of quantitative HPLC from the toluol solution.

TABLE D example 1 eq oxirane II eq triazole eq base temp./duration yieldof 1-triazolyl D1 R¹ = cylopropyl 1.3 NaOH/0.5 125° C./10 h 82% (R³)_(n)= 2-CF₃ (R⁴)_(m) = 4-Cl D2 R¹ = CH₃ 1.3 NaOH/1.3 125° C./6 h 86%(R³)_(n) = 2-CF₃ (R⁴)_(m) = 4-Cl D3 R¹ = cylopropyl 1.3 NaOH/1.3 125°C./12 h 75% (R³)_(n) = 2-CF₃ (R⁴)_(m) = 4-Cl D4 R¹ = CH₃ 1.3 KOH/0.3125° C./5.5 h 93% (R³)_(n) = 2-CF₃ (R⁴)_(m) = 4-Cl D5 R¹ = CH₃ 1.3NaOH/0.3 125° C./5 h 91% (R³)_(n) = 2-CF₃ (R⁴)_(m) = 4-Cl D6 R¹ = CH₃1.3 KOH/1.3 125° C./6 h 89% (R³)_(n) = 2-CF₃ (R⁴)_(m) = 4-Cl D7 R¹ =cylopropyl 1.3 KOH/1.3 125° C./16 h 56% (R³)_(n) = 2-CF₃ (R⁴)_(m) = 4-ClD8 R¹ = cylopropyl 1.3 KOH/0.3 125° C./12 h 76% (R³)_(n) = 2-CF₃(R⁴)_(m) = 4-Cl

E1) Comparative Example

To1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]cyclopropyl-methanone(0.13 mol) dissolved in 55 g dimethylsulfide together with 42 g aqueoustrimethylsulfonium-methylsulfate (86 wt-%, prepared according topExample A1) at 22° C., 15.7 g NaOH pellets (98 wt-%) (0.385 mol) wereadded under vigorous stirring. This led to an increase in temperature ofabout 5 to 6° C. Then, stirring was continued for 20 h at 38° C. Asample of the reaction solution showed incomplete conversion of theketon (detection by means of HPLC). Then, 199 g 20 wt-% NaCl solutionwere added at 30° C. After separation of the aqueous phase, the dimethylsulfide solution was concentrated by means of distillation of thesolvent at a temperature of up to 90° C. 59.7 g (about 47 wt-% product,determined with quantitative HPLC)2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane wereobtained; Yield: 66%

E2) Comparative Example

Use of 50% Ig Aqueous KOH Leads to Incomplete Conversion of Reagents

To1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]cyclopropyl-methanone(0.13 mol), dissolved in 55 g dimethylsulfide together with 42 g aqueoustrimethylsulfonium-methylsulfate (86 wt-%, prepared according to ExampleA1) at 22° C., 15.743 g 50% aqueous KOH (0.385 mol) were added undervigorous stirring. This led to an increase in temperature of about 5 to6° C. Then, stirring was continued for 32 h at 38° C. A sample of thereaction solution showed incomplete conversion of the keton (detectionby means of HPLC). Then, 199 g 20 wt-% NaCl solution were added at 30°C. After separation of the aqueous phase, the dimethyl sulfide solutionwas concentrated by means of distillation of the solvent at atemperature of up to 90° C. 53.5 g (about 34.5 wt-% product, determinedwith quantitative HPLC) of2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane wereobtained. Yield: 44%.

The invention claimed is:
 1. A crystalline form of2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-(1,2,4-triazol-1-yl)propane-2-olwhich, in an X-ray powder diffractogram at 25° C. using Cu—K_(α)radiation, shows at least six of the fifteen following reflections,given as 2θ values: 9.16±0.20, 13.95±0.20, 15.35±0.20, 16.04±0.20,16.51±0.20, 17.17±0.20, 18.26±0.20, 18.89±0.20, 20.59±0.20, 21.11±0.20,21.49±0.20, 22.33±0.20, 22.60±0.20, 23.26±0.20, 26.46±0.20.
 2. Anagrochemical composition containing the crystalline form as claimed inclaim 1 and an auxiliary.
 3. A method for controlling harmful fungi,which method comprises applying the crystalline form of claim 1 to thefungi or plants, soil, seeds or non-living materials.